Pyrrolo[2,3-d]pyrimidine derivatives

ABSTRACT

Described herein are pyrrolo{2,3-d}pyrimidine derivatives, their use as Janus Kinase (JAK) inhibitors, and pharmaceutical compositions containing them.

This is a Continuation of U.S. application Ser. No. 14/183,946, filedFeb. 19, 2014, which claims priority to U.S. Provisional ApplicationSer. No. 61/767,947, filed Feb. 22, 2013, the entire disclosure of whichis incorporated herein.

FIELD OF THE INVENTION

The present invention provides pharmaceutically activepyrrolo[2,3-d]pyrimidine compounds and analogues. Such compounds areuseful for inhibiting Janus Kinase (JAK). This invention also isdirected to compositions comprising methods for making such compounds,and methods for treating and preventing conditions mediated by JAK.

BACKGROUND OF THE INVENTION

Protein kinases are families of enzymes that catalyze thephosphorylation of specific residues in proteins, broadly classifiedinto tyrosine and serine/threonine kinases. Inappropriate kinaseactivity, arising from mutation, over-expression, or inappropriateregulation, dys-regulation or de-regulation, as well as over- orunder-production of growth factors or cytokines has been implicated inmany diseases, including but not limited to cancer, cardiovasculardiseases, allergies, asthma and other respiratory diseases, autoimmunediseases, inflammatory diseases, bone diseases, metabolic disorders, andneurological and neurodegenerative disorders such as Alzheimer'sdisease. Inappropriate kinase activity triggers a variety of biologicalcellular responses relating to cell growth, cell differentiation,survival, apoptosis, mitogenesis, cell cycle control, and cell mobilityimplicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes astargets for therapeutic intervention. In particular, the JAK family ofcellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play acentral role in cytokine signaling (Kisseleva et al., Gene, 2002, 285,1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to theirreceptors, cytokines activate JAK which then phosphorylate the cytokinereceptor, thereby creating docking sites for signaling molecules,notably, members of the signal transducer and activator of transcription(STAT) family that ultimately lead to gene expression. Numerouscytokines are known to activate the JAK family. These cytokines include,the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma,IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11, OSM, LIF,CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), gamma C family(IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3,IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptortyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupledreceptors (AT1).

There remains a need for new compounds that effectively and selectivelyinhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 isa member of the Janus family of protein kinases composed of JAK1, JAK2,JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Manycytokine receptors signal through pairs of JAK kinases in the followingcombinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/TYK2 or JAK2/JAK2.JAK1 is the most broadly paired JAK kinase in this context and isrequired for signaling by γ-common (IL-2Rγ) cytokine receptors, IL-6receptor family, Type I, II and III receptor families and IL-10 receptorfamily. Animal studies have shown that JAK1 is required for thedevelopment, function and homeostasis of the immune system. Modulationof immune activity through inhibition of JAK1 kinase activity can proveuseful in the treatment of various immune disorders (Murray, P. J. J.Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285, 1-24(2002); O'Shea, J. J., et al., Cell, 109, (suppl.) S121-S131 (2002))while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin(TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);Parganas E., et al., Cell, 93(3), 385-95 (1998)).

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I having thestructure:

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen orC₁-C₄ alkyl, wherein said alkyl is further optionally substituted withone or more substituents selected from the group consisting of halo,hydroxy, methoxy, amino, CF₃, and C₃-C₆ cycloalkyl; R² and R³ are eachindependently hydrogen, deuterium, C₁-C₆ linear or branched chain alkyl,C₃-C₆ cycloalkyl, C₁-C₆ linear or branched chain perfluoroalkyl, C₁-C₆linear or branched chain alkoxy, C₁-C₆ linear or branched chainperfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy,aminocarbonyl, aryl, heteroaryl, (aryl)C₁-C₆ linear or branched chainalkyl, (heteroaryl)C₁-C₆ linear or branched chain alkyl,(heterocyclic)C₁-C₆ linear or branched chain alkyl, (C₁-C₆ linear orbranched chain alkyl)aryl, (C₁-C₆ linear or branched chainalkyl)heteroaryl, (C₁-C₆ linear or branched chain alkyl)heterocyclic,(C₁-C₆ linear or branched chain alkoxyl)carbonyl, (C₁-C₆ linear orbranched chain alkyl)amino-carbonylamino, or (C₁-C₆ linear or branchedchain alkyl)aminocarbonyl; R⁴ is selected from hydrogen, deuterium,C₁-C₆ linear or branched chain alkyl, C₁-C₆ linear or branched chainperfluoroalkyl, aryl, and alkylaryl; X is selected from —NH— and—CR_(a)R_(b)—, where (a) R_(a) and R_(b) are independently hydrogen,deuterium, C₁-C₆ linear or branched chain alkyl, C₃-C₆ cycloalkyl, aryl,(aryl)C₁-C₆ linear or branched chain alkyl, heteroaryl, (C₁-C₆ linear orbranched chain alkyl)heteroaryl, (heteroaryl)C₁-C₆ linear or branchedchain alkyl, (heterocyclic)C₁-C₆ linear or branched chain alkyl, or (b)R_(a) and R_(b) together form a chain comprising —(CR_(c)R_(d))_(j)—,where R_(c) and R_(d) are independently hydrogen, deuterium, C₁-C₆linear or branched chain alkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, (C₁-C₆ linear or branched chainalkyl)heteroaryl, halo, CN, CF₃, hydroxyl, CONH₂, or SO₂CH₃; Y is -A-R⁵,where A is a bond, —(CH₂)_(k)— or —(CD₂)_(k)— and R⁵ is C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, or —NR_(a′)R_(b′), or isan unsaturated, saturated or partially saturated monocyclic or bicyclicring structure containing a total of five to eleven atoms having one tothree heteroatoms independently selected from the group consisting ofoxygen, nitrogen, and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl,aryl, or monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —OR_(e), —NR_(e)R_(f), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more substituents selected from the groupconsisting of halo, CN, hydroxyl, CONH₂, and SO₂CH₃, where (a) R_(a′)and R_(b′) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branchedchain alkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c′), or (b) R_(a′) and R_(b′) togetherform a chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl,(C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl,CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) andR_(f) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; j is 2, 3, 4 or5; k is 1, 2; 3, or 4; p is 0, 1 or 2; and, n is 1 or 2.

In other aspects, the present invention also provides:

pharmaceutical compositions which comprise a pharmaceutically acceptablecarrier and a compound of formula I;

methods for treating conditions or disorders including myositis,vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis,multiple sclerosis, major depression disorder, allergy, asthma,Sjogren's disease, dry eye syndrome, transplant rejection, cancer,inflammatory bowel disease, septic shock, cardiopulmonary dysfunction,acute respiratory disease, or cachexia by administering to a subject inneed a therapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof;

methods for treating conditions or disorders including atopicdermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, otherpruritic conditions, allergic reactions including allergic dermatitis inmammal, horse allergic diseases including bite hypersensitivity, summereczema, sweet itch in horses, heaves, inflammatory airway disease,recurrent airway obstruction, airway hyper-responsiveness, and chronicobstruction pulmonary disease by administering to a mammal in need atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof; and,

methods for the preparation of compounds of the present invention. Thepresent invention will be further understood from the followingdescription given by way of example only. The present invention isdirected to a class of pyrrolo[2,3-d]pyrimidine derivatives. Inparticular, the present invention is directed topyrrolo[2,3-d]pyrimidine compounds useful as inhibitors of JAK, andparticularly JAK1. While the present invention is not so limited, anappreciation of various aspects of the invention will be gained throughthe following discussion and the examples.

The term “alkyl”, alone or in combination, means an acyclic, saturatedhydrocarbon group of the formula C_(n)H_(2n+1) which may be linear orbranched. Examples of such groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyland hexyl. Unless otherwise specified, an alkyl group comprises from 1to 6 carbon atoms. The carbon atom content of alkyl and various otherhydrocarbon-containing moieties is indicated by a prefix designating alower and upper number of carbon atoms in the moiety, that is, theprefix C_(i)-C_(j) indicates a moiety of the integer “i” to the integer“j” carbon atoms, inclusive. Thus, for example, C₁-C₆ alkyl refers toalkyl of one to six carbon atoms, inclusive.

The term “hydroxy,” as used herein, means an OH radical. The term“heterocyclic” refers to a saturated or partially saturated (i.e. nonaromatic) heterocycle which may be attached via a ring nitrogen atom(when the heterocycle is attached to a carbon atom) or a ring carbonatom (in all cases). Equally, when substituted, the substituent may belocated on a ring nitrogen atom (if the substituent is joined through acarbon atom) or a ring carbon atom (in all cases). Specific examplesinclude oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,piperazinyl, azepanyl, oxepanyl, oxazepanyl and diazepinyl.

The term “aryl” refers to an aromatic monocyclic or bicyclic hydrocarbonwhich may be attached via a ring carbon atom. Equally, when substituted,the substituent may be located on a ring carbon atom. Specific examplesinclude phenyl, toluyl, xylyl, trimethylphenyl, and naphthyl. Examplesof aryl substituents include alkyl, hydroxyl, halo, nitrile, alkoxy,trifluoromethyl, carboxamido, SO₂Me, benzyl, and substituted benzyl.

The term “heteroaryl” refers to an aromatic heterocycle which may beattached via a ring carbon atom (in all cases) or a ring nitrogen atomwith an appropriate valency (when the heterocycle is attached to acarbon atom). Equally, when substituted, the substituent may be locatedon a ring carbon atom (in all cases) or a ring nitrogen atom with anappropriate valency (if the substituent is joined through a carbonatom). Specific examples include thienyl, furanyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyland pyrazinyl. The term “cycloalkyl” means a monocyclic, saturatedhydrocarbon group of the formula C_(n)H_(2n−1). Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.Unless otherwise specified, a cycloalkyl group comprises from 3 to 8carbon atoms.

The terms “halo” and “halogen” refer to fluoride (F), chloride (Cl),bromide (Br) or iodide (I).

The term “mammal” refers to human, livestock or companion animals.

The term “companion animal” or “companion animals” refers to animalskept as pets or household animal. Examples of companion animals includedogs, cats, and rodents including hamsters, guinea pigs, gerbils and thelike, rabbits, ferrets and birds.

The term “livestock” refers to animals reared or raised in anagricultural setting to make products such as food or fiber, or for itslabor. In some embodiments, livestock are suitable for consumption bymammals, for example humans. Examples of livestock animals includecattle, goats, horses, pigs, sheep, including lambs, and rabbits, aswell as birds, such as chickens, ducks and turkeys.

The term “treating” or “treatment” means an alleviation of symptomsassociated with a disease, disorder or condition, or halt of furtherprogression or worsening of those symptoms. Depending on the disease andcondition of the patient, the term “treatment” as used herein mayinclude one or more of curative, palliative and prophylactic treatment.Treatment can also include administering a pharmaceutical formulation ofthe present invention in combination with other therapies.

The term “therapeutically-effective” indicates the capability of anagent to prevent, or improve the severity of, the disorder, whileavoiding adverse side effects typically associated with alternativetherapies. The phrase “therapeutically-effective” is to be understood tobe equivalent to the phrase “effective for the treatment, prevention, oramelioration”, and both are intended to qualify the amount of each agentfor use in the combination therapy which will achieve the goal ofimprovement in the severity of cancer, cardiovascular disease, or painand inflammation and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies.

“Pharmaceutically acceptable” means suitable for use in mammals,companion animals or livestock animals.

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to novel compounds which are selectiveJAK1 modulators useful for the treatment of diseases and conditionsassociated with dysregulation of the JAK1. The present invention furtherprovides pharmaceutical compositions comprising such JAK1 modulators aswell as methods of treating and/or preventing such diseases andconditions. Accordingly, the present invention provides a compound offormula I having the structure:

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen orC₁-C₄ alkyl, wherein said alkyl is further optionally substituted withone or more substituents selected from the group consisting of halo,hydroxy, methoxy, amino, CF₃, and C₃-C₆ cycloalkyl; R² and R³ are eachindependently hydrogen, deuterium, C₁-C₆ linear or branched chain alkyl,C₃-C₆ cycloalkyl, C₁-C₆ linear or branched chain perfluoroalkyl, C₁-C₆linear or branched chain alkoxy, C₁-C₆ linear or branched chainperfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy,aminocarbonyl, aryl, heteroaryl, (aryl)C₁-C₆ linear or branched chainalkyl, (heteroaryl)C₁-C₆ linear or branched chain alkyl,(heterocyclic)C₁-C₆ linear or branched chain alkyl, (C₁-C₆ linear orbranched chain alkyl)aryl, (C₁-C₆ linear or branched chainalkyl)heteroaryl, (C₁-C₆ linear or branched chain alkyl)heterocyclic,(C₁-C₆ linear or branched chain alkoxyl)carbonyl, (C₁-C₆ linear orbranched chain alkyl)amino-carbonylamino, or (C₁-C₆ linear or branchedchain alkyl)aminocarbonyl; R⁴ is selected from hydrogen, deuterium,C₁-C₆ linear or branched chain alkyl, C₁-C₆ linear or branched chainperfluoroalkyl, aryl, and alkylaryl; X is selected from —NH— and—CR_(a)R_(b)—, where (a) R_(a) and R_(b) are independently hydrogen,deuterium, C₁-C₆ linear or branched chain alkyl, C₃-C₆ cycloalkyl, aryl,(aryl)C₁-C₆ linear or branched chain alkyl, heteroaryl, (C₁-C₆ linear orbranched chain alkyl)heteroaryl, (heteroaryl)C₁-C₆ linear or branchedchain alkyl, (heterocyclic)C₁-C₆ linear or branched chain alkyl, or (b)R_(a) and R_(b) together form a chain comprising —(CR_(c)R_(d))_(j)—,where R_(c) and R_(d) are independently hydrogen, deuterium, C₁-C₆linear or branched chain alkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, (C₁-C₆ linear or branched chainalkyl)heteroaryl, halo, CN, CF₃, hydroxyl, CONH₂, or SO₂CH₃; Y is -A-R⁵,where A is a bond, —(CH₂)_(k)— or —(CD₂)_(k)— and R⁵ is C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, or —NR_(a′)R_(b′), or isan unsaturated, saturated or partially saturated monocyclic or bicyclicring structure containing a total of five to eleven atoms having one tothree heteroatoms independently selected from the group consisting ofoxygen, nitrogen, and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl,aryl, or monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —OR_(e), —NR_(e)R_(f), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more substituents selected from the groupconsisting of halo, CN, hydroxyl, CONH₂, and SO₂CH₃, where (a) R_(a′)and R_(b′) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branchedchain alkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c′), or (b) R_(a′) and R_(b′) togetherform a chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl,(C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl,CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) andR_(f) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; j is 2, 3, 4 or5; k is 1, 2; 3, or 4; p is 0, 1 or 2; and, n is 1 or 2. In oneembodiment, the invention provides a compound of formula IA having thestructure:

or a pharmaceutically acceptable salt thereof, wherein Y is -A-R⁵, whereA is a bond, —(CH₂)_(k)— or —(CD₂)_(k)— and R⁵ is C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, or —NR_(a′)R_(b′), or isan unsaturated, saturated or partially saturated monocyclic or bicyclicring structure containing a total of five to eleven atoms having one tothree heteroatoms independently selected from the group consisting ofoxygen, nitrogen, and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl,aryl, or monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —OR_(e), —NR_(e)R_(f), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more substituents selected from the groupconsisting of halo, CN, hydroxyl, CONH₂, and SO₂CH₃, where (a) R_(a′)and R_(b′) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branchedchain alkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c′), or (b) R_(a′) and R_(b′) togetherform a chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl,(C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl,CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) andR_(f) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; j is 2, 3, 4 or5; k is 1, 2; 3, or 4; and, p is 0, 1 or 2.

In one embodiment, the invention provides a compound of formula IAwherein A is a bond and R⁵ is a C₁-C₆ linear or branched chain alkyl,C₃-C₆ cycloalkyl or aryl. In another embodiment, the invention providesa compound of formula IA wherein A is a bond or —(CH₂)_(k)—, and R⁵ isC₃-C₆ cycloalkyl wherein said C₃-C₆ cycloalkyl is further optionallysubstituted with one or more substituents selected from the groupconsisting of halo, C₁-C₆ linear or branched chain alkyl, and CN wheresaid alkyl and cycloalkyl may be optionally substituted with one or moresubstituents selected from the group consisting of halo, CN, hydroxyl,CONH₂, and SO₂CH₃; where k is 1, 2, or 3. In yet another embodiment, theinvention provides a compound of formula IA wherein A is a bond or—(CH₂)_(k)—, and R⁵ is an unsaturated, saturated or partially saturatedmonocyclic or bicyclic ring structure containing a total of five toeleven atoms having one to three heteroatoms independently selected fromthe group consisting of oxygen, nitrogen, and sulfur, wherein saidalkyl, C₃-C₆ cycloalkyl, aryl, or monocyclic or bicyclic ring structureis further optionally substituted with one or more substituents selectedfrom the group consisting of deuterium, halo, C₁-C₆ linear or branchedchain alkyl, CN, hydroxyl, CF₃, —NR_(a′)R_(b′), —OR_(e), —S(O)_(p)R_(e)and C₃-C₆ cycloalkyl; where k is 1, 2, or 3.

In another embodiment, the invention provides the compound of formula IBhaving the structure:

or a pharmaceutically acceptable salt thereof, wherein (a) R_(a′) andR_(b′) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c′) or (b) R_(a′) and R_(b′) togetherform a chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl,(C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl,CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) andR_(f) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; or, (c) R_(a′)and R_(b′) together form an unsaturated, saturated or partiallysaturated monocyclic or bicyclic ring structure containing a total offive to eleven atoms having one to three heteroatoms independentlyselected from the group consisting of oxygen, nitrogen, and sulfur,wherein said monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —NR_(a′)R_(b′), —OR_(e), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl; j is 2, 3, 4 or 5; and, p is 0, 1 or 2.

In another embodiment, the invention provides the compound of formula IChaving the structure:

or a pharmaceutically acceptable salt thereof, wherein (a) R_(a′) andR_(b′) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R, or (b) R_(a′) and R_(b′) together form achain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′) areindependently hydrogen, deuterium, C₁-C₆ linear or branched chain alkyl,aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl, (C₁-C₆linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF₃,CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) and R_(f)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; or, (c) R_(a′)and R_(b′) together form an unsaturated, saturated or partiallysaturated monocyclic or bicyclic ring structure containing a total offive to eleven atoms having one to three heteroatoms independentlyselected from the group consisting of oxygen, nitrogen, and sulfur,wherein said monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —OR_(e), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl; j is 2, 3,4 or 5; and, p is 0, 1 or 2.

In another embodiment, the invention provides the compound of formula IDhaving the structure:

or a pharmaceutically acceptable salt thereof, wherein

Y is -AR⁵, where A is a bond or —(CH₂)_(k)—, and R⁵ is C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, or is an unsaturated,saturated or partially saturated monocyclic or bicyclic ring structurecontaining a total of five to eleven atoms having one to threeheteroatoms independently selected from the group consisting of oxygen,nitrogen, and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl, aryl, ormonocyclic or bicyclic ring structure is further optionally substitutedwith one or more substituents selected from the group consisting ofdeuterium, halo, C₁-C₆ linear or branched chain alkyl, CN, hydroxyl,CF₃, —OR_(e), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CONH₂, andSO₂CH₃, where (a) R_(a′) and R_(b′) are independently hydrogen,deuterium, C₁-C₆ linear or branched chain alkyl, C₃-C₆ cycloalkyl, aryl,(aryl)C₁-C₆ linear or branched chain alkyl, heteroaryl, (C₁-C₆ linear orbranched chain alkyl)heteroaryl, (heteroaryl)C₁-C₆ linear or branchedchain alkyl, (heterocyclic)C₁-C₆ linear or branched chain alkyl, wheresaid alkyl and cycloalkyl may be optionally substituted with one or moreR_(c′), or (b) R_(a′) and R_(b′) together form a chain comprising—(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′) are independentlyhydrogen, deuterium, C₁-C₆ linear or branched chain alkyl, aryl, (C₁-C₆linear or branched chain alkyl)aryl, heteroaryl, (C₁-C₆ linear orbranched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF₃, CONH₂,—OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) and R_(f) whereare independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; j is 2, 3, 4 or5; k is 1, 2, or 3; and, p is 0, 1 or 2. In one embodiment, theinvention provides the compound of formula ID wherein R⁵ is a C₁-C₆linear or branched chain alkyl or C₃-C₆ cycloalkyl.

In another embodiment, the invention provides the compound of formula offormula ID wherein A is a bond or —(CH₂)_(k)—, and R⁵ is an unsaturated,saturated or partially saturated monocyclic or bicyclic ring structurecontaining a total of five to eleven atoms having one to threeheteroatoms independently selected from the group consisting of oxygen,nitrogen, and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl, aryl, ormonocyclic or bicyclic ring structure is further optionally substitutedwith one or more substituents selected from the group consisting ofdeuterium, halo, C₁-C₆ linear or branched chain alkyl, CN, hydroxyl,CF₃, —NR_(a′)R_(b′), —OR_(e), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl; whereR_(e) and R_(f) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, or C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CF₃, andCONH₂; k is 1, 2, or 3; and, p is 0, 1 or 2. In another embodiment, theinvention provides the compound of formula I wherein R⁵ is anunsaturated ring structure containing a total of five to eleven atomshaving one or two heteroatoms independently selected from the groupconsisting of oxygen, nitrogen, and sulfur. In other embodiments, theinvention provides the compound of formula I wherein R⁵ is furyl,thiofuryl, pyrrolyl, pyrazolyl, oxazolyl, azetidinyl, piperidinyl orthiazolyl, optionally substituted by one or two methyl.

In another embodiment, the invention provides the compound selected fromthe group consisting of:

-   4-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}pyrid    ine-2-sulfonamide;-   2,2,2-trifluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-ethanesulfonamide;-   2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide;-   N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide;-   1-cyclopropyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methanesulfonamide;-   N-{cis-3-[(butylsulfonyl)methyl]cyclobutyl}-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   1-cyclopropyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-azetidine-3-sulfonamide;-   3-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-azetidine-1-sulfonamide;-   (1R,5S)—N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-6-oxa-3-azabicyclo[3.1.1]heptane-3-sulfonamide;-   (3R)-3-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-pyrrolidine-1-sulfonamide;-   (3S)-3-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-pyrrolidine-1-sulfonamide;-   N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1-(oxetan-3-yl)methanesulfonamide;-   1-(3,3-difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methanesulfonamide;-   trans-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}cyclo-butanesulfonamide;-   cis-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}cyclobutane-sulfonamide;-   N-[cis-3-({[(3,3-difluorocyclobutyl)methyl]sulfonyl}methyl)cyclobutyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   (1S,5S)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-3-azabicyclo[3.1.0]hexane-3-sulfonamide;-   (1R,5R)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-3-azabicyclo[3.1.0]hexane-3-sulfonamide;-   (3R)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyrrolidine-3-carbonitrile;-   1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]-4-(trifluoromethyl)piperidin-4-ol;-   N-(cis-3-{[(4,4-difluoropiperidin-1-yl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   (3S)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyrrolidine-3-carbonitrile;-   N-(cis-3-{[(3-chloro-4-fluorophenyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   N-(cis-3-{[(2-cyclopropylethyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   N-methyl-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfonyl}methyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   3,3-difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-cyclobutane-sulfonamide;-   1-[3-(cyanomethyl)oxetan-3-yl]-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methanesulfonamide;-   cis-3-(cyanomethyl)-3-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-cyclobutanesulfonamide;-   trans-3-(cyanomethyl)-3-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}cyclobutanesulfonamide;-   N-(2-cyanoethyl)-N-methyl-N′-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}sulfuric    diamide;-   N-{(1S,3R)-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclopentyl}propane-1-sulfonamide;-   3-(2-hydroxypropan-2-yl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}benzene-sulfonamide;-   N-(cyclopropylmethyl)-N′-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}sulfuric    diamide;-   N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-4-(1H-pyrazol-3-yl)piperidine-1-sulfonamide;-   2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-sulfonamide;-   2-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)-sulfonyl]pyridine-4-carbonitrile;-   (1S,3S)-3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)-sulfonyl]cyclopentanecarbonitrile;-   (1R,3R)-3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methyl)sulfonyl]cyclopentanecarbonitrile;-   1-cyclopropyl-N-{trans-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methane    sulfonamide;-   3-cyano-N-{trans-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-pyrrolidine-1-sulfonamide;-   N-methyl-N-{trans-3-[(propylsulfonyl)methyl]cyclobutyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine;    and,-   2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1,3-thiazole-5-sulfonamide;    or, a pharmaceutically acceptable salt thereof.-   In another embodiment, the invention provides the compound selected    from the group consisting of:-   1-(3,3-difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclo-butyl}methanesulfonamide;-   trans-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}cyclo-butanesulfonamide;-   N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide;-   3,3-difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-cyclobutane-sulfonamide;    and,-   N-{(1S,3R)-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclopentyl}propane-1-sulfonamide;    or, a pharmaceutically acceptable salt thereof.

In other embodiments, the invention provides the compound selected fromthe group consisting of:

-   (3R)-3-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}pyrrolidine-1-sulfonamide;-   (1R,5S)—N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-6-oxa-3-azabicyclo[3.1.1]heptane-3-sulfonamide;-   (1S,5S)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-3-azabicyclo[3.1.0]hexane-3-sulfonamide;-   N-(2-cyanoethyl)-N-methyl-N′-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}sulfuric    diamide; and,-   2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-sulfonamide;    or, a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides the compound selected fromthe group consisting of:

-   (3R)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)-sulfonyl]pyrrolidine-3-carbonitrile;-   1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]-4-(trifluoromethyl)piperidin-4-ol;-   N-(cis-3-{[(4,4-difluoropiperidin-1-yl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;-   (3S)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)-sulfonyl]pyrrolidine-3-carbonitrile;    and,

or, a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention provides the compound selectedfrom the group consisting of:

-   (1R,3R)-3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)-sulfonyl]cyclo-pentanecarbonitrile;-   (1S,3S)-3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methyl)sulfonyl]cyclo-pentanecarbonitrile;-   2-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)-sulfonyl]pyridine-4-carbonitrile;-   N-[cis-3-({[(3,3-difluorocyclobutyl)methyl]sulfonyl}methyl)cyclobutyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;    and,-   N-{cis-3-[(butylsulfonyl)methyl]cyclobutyl}-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;    or, a pharmaceutically acceptable salt thereof.

Particularly preferred embodiments include2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1,3-thiazole-5-sulfonamide,N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide;N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1-oxetan-3-ylmethanesulfonamide;1-(3,3-difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methanesulfonamide;3,3-difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}cyclobutanesulfonamide;trans-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-cyclobutanesulfonamide;(1S,5S)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-3-azabi-cyclo[3.1.0]hexane-3-sulfonamide;and,(3S)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyrrolidine-3-carbonitrile;or, a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical or a veterinarycomposition comprising a compound of formula I, IA, IB, IC or ID, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention also provides a method of treating a disorder orcondition related to dysregulation of JAK, and particularly of JAK1, ina subject, comprising administering to the subject a therapeuticallyeffective amount of the compound having the structure of formula I, IA,IB, IC or ID, or a pharmaceutically acceptable salt thereof. In certainembodiments, the disorder or condition treated by the method is selectedfrom among rheumatoid arthritis, myositis, vasculitis, pemphigus,Crohn's disease, ulcerative colitis, Alzheimer's disease, lupus,nephritis, psoriasis, atopic dermatitis, autoimmune thyroid disorders,multiple sclerosis, major depression disorder, allergy, asthma,Sjogren's disease, dry eye syndrome, organ transplant rejection, xenotransplantation, Type I diabetes and complications from diabetes,cancer, leukemia, T cell acute lymphoblastic leukemia, adult T cellleukemia activated B-cell like, diffuse large B cell lymphoma,inflammatory bowel disease, septic shock, cardiopulmonary dysfunction,chronic pulmonary obstructive disorder, acute respiratory disease, andcachexia comprising the step of administering to a subject an effectiveamount of a composition comprising a compound of formula I, IA, IB, ICor ID. In certain embodiments, the therapeutically effective amount usedin accord with the method is from 0.01 mg/kg of body weight/day to 100mg/kg of body weight/day. In certain other embodiments, thetherapeutically effective amount used in accord with the method is thetherapeutically effective amount is from 0.1 mg/kg of body weight/day to10 mg/kg of body weight/day. In the practice of the method, the compoundof formula I is preferably selected fromN-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide,N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1-oxetan-3-ylmethanesulfonamide;1-(3,3-difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methanesulfonamide;3,3-difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}cyclobutanesulfonamide;trans-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-cyclobutanesulfonamide;(1S,5S)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-3-azabi-cyclo[3.1.0]hexane-3-sulfonamide;and,(3S)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyrrolidine-3-carbonitrile;or a pharmaceutically acceptable salt thereof.

The present invention further provides a method for treating orpreventing a disorder or condition selected from atopic dermatitis,eczema, scleroderma, pruritus, other pruritic conditions, allergicreactions including allergic dermatitis in mammal, horse allergicdiseases including bite hypersensitivity, summer eczema, sweet itch inhorses, heaves, inflammatory airway disease, recurrent airwayobstruction, and airway hyper-responsiveness by administering to amammal in need a therapeutically effective amount of a compound offormula I, IA, IB, IC or ID, or a pharmaceutically acceptable saltthereof.

In certain embodiments, the therapeutically effective amount used inaccord with the method is from 0.01 mg/kg of body weight/day to 100mg/kg of body weight/day.

In certain other embodiments, the therapeutically effective amount usedin accord with the method is wherein the therapeutically effectiveamount is from 0.1 mg/kg of body weight/day to 10 mg/kg of bodyweight/day. In accord with the method, the mammal treated with thecompound of the invention is selected from companion animals, dogs, andlivestock. In certain embodiments, the compound of formula I, IA, IB, ICor ID, or a pharmaceutically acceptable salt thereof, may beadministered in accord with the method orally, parenterally, ortopically.

In the practice of the method, the compound of formula I is preferablyselected fromN-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide;N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1-oxetan-3-ylmethanesulfonamide;1-(3,3-difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methanesulfonamide;3,3-difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}cyclobutanesulfonamide;trans-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-cyclobutanesulfonamide;(1S,5S)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-3-azabi-cyclo[3.1.0]hexane-3-sulfonamide;and,(3S)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyrrolidine-3-carbonitrile;or, a pharmaceutically acceptable salt thereof.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. It will be appreciatedby those skilled in the art that the compound of formula I, IA, IB, ICor ID can exist as cis- and trans-achiral diastereomers.

Included within the scope of the described compounds are all isomers(e.g. cis-, trans-, or diastereomers) of the compounds described hereinalone as well as any mixtures. All of these forms, includingenantiomers, diastereomers, cis, trans, syn, anti, solvates (includinghydrates), tautomers, and mixtures thereof, are included in thedescribed compounds. Stereoisomeric mixtures, e.g. mixtures ofdiastereomers, can be separated into their corresponding isomers in aknown manner by means of suitable separation methods. Diastereomericmixtures for example may be separated into their individualdiastereomers by means of fractionated crystallization, chromatography,solvent distribution, and similar procedures. This separation may takeplace either at the level of one of the starting compounds or in acompound of formula I, IA, IB, IC or ID itself. Enantiomers may beseparated through the formation of diastereomeric salts, for example bysalt formation with an enantiomer-pure chiral acid, or by means ofchromatography, for example by HPLC, using chromatographic substrateswith chiral ligands.

In therapeutic use for treating disorders in a mammal, a compound of thepresent invention or its pharmaceutical compositions can be administeredorally, parenterally, topically, rectally, transmucosally, orintestinally. Parenteral administrations include indirect injections togenerate a systemic effect or direct injections to the afflicted area.Topical administrations include the treatment of skin or organs readilyaccessible by local application, for example, eyes or ears. It alsoincludes transdermal delivery to generate a systemic effect. The rectaladministration includes the form of suppositories. The preferred routesof administration are oral and parenteral.

Pharmaceutically acceptable salts of the compounds of formula I, IA, IB,IC or ID include the acid addition and base salts thereof. Suitable acidaddition salts are formed from acids which form non-toxic salts.Examples include the acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate,cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts: Properties, Selection, and Use byStahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula I, IA, IB, ICor ID may be prepared, respectively, by one or more of three methods:(i) by reacting the compound of formula I, IA, IB, IC or ID with thedesired acid or base; (ii) by removing an acid- or base-labileprotecting group from a suitable precursor of the compound of formula I,IA, IB, IC or ID or by ring-opening a suitable cyclic precursor, forexample, a lactone or lactam, using the desired acid or base; or (iii)by converting one salt of the compound of formula I, IA, IB, IC or ID toanother by reaction with an appropriate acid or base or by means of asuitable ion exchange column. All three reactions are typically carriedout in solution. The resulting salt may precipitate out and be collectedby filtration or may be recovered by evaporation of the solvent. Thedegree of ionization in the resulting salt may vary from completelyionized to almost non-ionized.

Pharmaceutical compositions of the present invention may be manufacturedby methods well known in the art, e.g., by means of conventional mixing,dissolving, granulation, dragee-making, levigating, emulsifying,encapsulating, entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morepharmaceutically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compound intopreparations, which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticallyacceptable excipients and carriers are generally known to those skilledin the art and are thus included in the instant invention. Suchexcipients and carriers are described, for example, in “Remington'sPharmaceutical Sciences” Mack Pub. Co., New Jersey (1991). Theformulations of the invention can be designed to be short-acting,fast-releasing, long-acting, and sustained-releasing. Thus, thepharmaceutical formulations can also be formulated for controlledrelease or for slow release.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose, i.e., control or thetreatment of disorders or diseases. More specifically, a therapeuticallyeffective amount means an amount of compound effective to prevent,alleviate or ameliorate symptoms/signs of disease or prolong thesurvival of the subject being treated.

The quantity of active component, which is the compound of thisinvention, in the pharmaceutical composition and unit dosage formthereof, may be varied or adjusted widely depending upon the manner ofadministration, the potency of the particular compound and the desiredconcentration. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art. Generally, thequantity of active component will range between 0.01% to 99% by weightof the composition.

Generally, a therapeutically effective amount of dosage of activecomponent will be in the range of about 0.01 to about 100 mg/kg of bodyweight/day, preferably about 0.1 to about 10 mg/kg of body weight/day,more preferably about 0.3 to 3 mg/kg of body weight/day, even morepreferably about 0.3 to 1.5 mg/kg of body weight/day It is to beunderstood that the dosages may vary depending upon the requirements ofeach subject and the severity of the disorders or diseases beingtreated.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Also, it is to be understood that the initial dosage administered may beincreased beyond the above upper level in order to rapidly achieve thedesired plasma concentration. On the other hand, the initial dosage maybe smaller than the optimum and the daily dosage may be progressivelyincreased during the course of treatment depending on the particularsituation. If desired, the daily dose may also be divided into multipledoses for administration, e.g., two to four times per day.

Compounds of the present invention are directed topyrrolo[2,3-d]pyrimidine compounds useful as Janus Kinase inhibitors(JAK-i). They are useful as therapeutic agents in connection with thetreating or preventing a disorder or condition selected from rheumatoidarthritis, myositis, vasculitis, pemphigus, Crohn's disease, ulcerativecolitis, Alzheimer's disease, lupus, nephritis, psoriasis, atopicdermatitis, autoimmune thyroid disorders, multiple sclerosis, majordepression disorder, allergy, asthma, Sjogren's disease, dry eyesyndrome, organ transplant rejection, xeno transplantation, Type Idiabetes and complications from diabetes, cancer, leukemia, T cell acutelymphoblastic leukemia, adult T cell leukemia activated B-cell like,diffuse large B cell lymphoma, inflammatory bowel disease, septic shock,cardiopulmonary dysfunction, chronic pulmonary obstructive disorder,acute respiratory disease, cachexia, and other indications whereimmunosuppression/immunomodulation would be desirable, comprising thestep of administering to a subject an effective amount of a compound ofthe invention.

There are substantial needs for safe and efficacious agents to controldisorders related to JAK, such as atopic dermatitis, both in human andanimals. The market for treating atopic dermatitis in animals iscurrently dominated by corticosteroids, which cause distressing andundesirable side effects in animals, specifically in companion animalssuch as dogs. Antihistamines are also used, but are poorly effective. Acanine formulation of cyclosporine (ATOPICA™) is currently beingmarketed for atopic dermatitis, but is expensive and has a slow onset ofefficacy. In addition, there are GI toleration issues with ATOPICA™.Compounds of the present invention are JAK inhibitors with selectiveefficacy against JAK1. These compounds are expected to provide analternative to steroid usage and provide resolution of chronic pruritusand inflammation that would either persist in atopic dermatitis orslowly regress following removal of allergen or causative agent, such asfleas in flea-allergic dermatitis.

Compounds of the present invention may be administered in apharmaceutically acceptable form either alone or in combination with oneor more additional agents which modulate a mammalian immune system orwith anti-inflammatory agents. These agents may include but are notlimited to cyclosporin A (e.g., Sandimmune™ or Neoral™, rapamycin,FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.,Cellcept™, azathioprine (e.g., Imuran™), daclizumab (e.g., Zenapax™),OKT3 (e.g., Orthocolone™), AtGam, aspirin, acetaminophen, ibuprofen,naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisoloneor dexamethasone). These agents may be administered as part of the sameor separate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice known to one skilled inthe art.

Accordingly, the invention provides methods of treating or preventing adisease, condition or disorder associated with JAK in a subject, such asa human or non-human mammal, comprising administering an effectiveamount of one or more compounds described herein to the subject.Suitable subjects that can be treated include domestic or wild animals,companion animals, such as dogs, cats, horses and the like; livestockincluding, cows and other ruminants, pigs, poultry, rabbits and thelike; primates, for example monkeys, such as rhesus monkeys andcynomolgus (also known as crab-eating or long-tailed) monkeys,marmosets, tamarins, chimpanzees, macaques and the like; and rodents,such as rats, mice, gerbils, guinea pigs and the like. In oneembodiment, the compound is administered in a pharmaceuticallyacceptable form, optionally in a pharmaceutically acceptable carrier.

Conditions in which selective targeting of the JAK pathway or modulationof the JAK kinases, particularly JAK1, are contemplated to betherapeutically useful include, arthritis, asthma, autoimmune diseases,cancers or tumors, diabetes, certain eye diseases, disorders orconditions, inflammation, intestinal inflammations, allergies orconditions, neurodegenerative diseases, psoriasis, and transplantrejection. Conditions which can benefit from selective inhibition ofJAK1 are discussed in greater detail below.

Accordingly, the compound of formula I, IA, IB, IC or ID, or itspharmaceutically acceptable salts, and pharmaceutical compositionsthereof can be used to treat a variety of conditions or diseases such asthe following:

Arthritis, including rheumatoid arthritis, juvenile arthritis, andpsoriatic arthritis;

Autoimmune diseases or disorders, including those designated as singleorgan or single cell-type autoimmune disorders, for example Hashimoto'sthyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritisof pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, autoimmune thrombocytopenia, sympatheticophthalmia, myasthenia gravis, Graves' disease, primary biliarycirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy, those designated as involving systemicautoimmune disorder, for example systemic lupus erythematosis,rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome,polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa,multiple sclerosis and bullous pemphigoid, and additional autoimmunediseases, which can be 0-cell (humoral) based or T-cell based, includingCogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis,autoimmune alopecia, Type I or juvenile onset diabetes, or thyroiditis;

Cancers or tumors, including alimentary/gastrointestinal tract cancer,colon cancer, liver cancer, skin cancer including mast cell tumor andsquamous cell carcinoma, breast and mammary cancer, ovarian cancer,prostate cancer, lymphoma, leukemia, including acute myelogenousleukemia and chronic myelogenous leukemia, kidney cancer, lung cancer,muscle cancer, bone cancer, bladder cancer, brain cancer, melanomaincluding oral and metastatic melanoma, Kaposi's sarcoma, myelomasincluding multiple myeloma, myeloproliferative disorders, proliferativediabetic retinopathy, or angiogenic-associated disorders including solidtumors;

Diabetes, including Type I diabetes or complications from diabetes;

Eye diseases, disorders or conditions including autoimmune diseases ofthe eye, keratoconjunctivitis, vernal conjunctivitis, uveitis includinguveitis associated with Behcet's disease and lens-induced uveitis,keratitis, herpetic keratitis, conical keratitis, corneal epithelialdystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis,Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome,keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis,sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis,allergic conjunctivitis, or ocular neovascularization;

Intestinal inflammations, allergies or conditions including Crohn'sdisease and/or ulcerative colitis, inflammatory bowel disease, celiacdiseases, proctitis, eosinophilic gastroenteritis, or mastocytosis;

Neurodegenerative diseases including motor neuron disease, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, cerebral ischemia, or neurodegenerative diseasecaused by traumatic injury, strike, glutamate neurotoxicity or hypoxia;ischemic/reperfusion injury in stroke, myocardial ischemica, renalischemia, heart attacks, cardiac hypertrophy, atherosclerosis andarteriosclerosis, organ hypoxia, or platelet aggregation;

Skin diseases, conditions or disorders including atopic dermatitis,eczema, psoriasis, scleroderma, pruritus or other pruritic conditions;

Allergic reactions including allergic dermatitis in mammal (includinghorse allergic diseases such as bite hypersensitivity), summer eczema,sweet itch in horses, heaves, inflammatory airway disease, recurrentairway obstruction, airway hyper-responsiveness, or chronic obstructionpulmonary disease;

Asthma and other obstructive airways diseases, including chronic orinveterate asthma, late asthma, bronchitis, bronchial asthma, allergicasthma, intrinsic asthma, extrinsic asthma, or dust asthma;

Transplant rejection, including pancreas islet transplant rejection,bone marrow transplant rejection, graft-versus-host disease, organ andcell transplant rejection such as bone marrow, cartilage, cornea, heart,intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast,nerve, pancreas, skin, small intestine, or trachea, or xenotransplantation; and

Another embodiment provides a method of selectively inhibiting a JAK1enzyme, which includes contacting the JAK enzyme with either anon-therapeutic amount or a therapeutically effective amount of one ormore of the presently taught compounds. Such methods can occur in vivoor in vitro. In vitro contact can involve a screening assay to determinethe efficacy of the one or more compounds against a selected enzyme atvarious amounts or concentrations. In vivo contact with atherapeutically effective amount of the one or more compounds caninvolve treatment of a described disease, disorder or condition orprophylaxis of organ transplant rejection in the animal in which thecontact occurs. The effect of the one or more compounds on the JAKenzyme and/or host animal can also be determined or measured. Methodsfor determining JAK activity include those described in the Examples aswell as those disclosed in WO99/65908, WO 99/65909, WO01/42246,WO02/00661, WO02/096909, WO2004/046112 and WO2007/012953.

Chemical Synthesis

The following schemes and written descriptions provide general detailsregarding the preparation of the compounds of the invention.

Sulfonamides

Compounds of formula I, wherein p is 2, X is NH, Y is AR⁵, and A is abond, may be prepared according to Scheme 1.

It will be apparent to those skilled in the art that sensitivefunctional groups (PG) may need to be protected and deprotected duringthe synthesis of a compound of the invention. Protection anddeprotection may be achieved by conventional methods, as described, forexample, in “Protective Groups in Organic Synthesis” by T. W. Greene andP. G. M. Wuts, John Wiley & Sons Inc. (1999), and references therein.Thus, in Scheme 1, Step 1, a compound of formula II, wherein Q¹ ishalogen, is treated with a protecting agent to provide a compound offormula III, wherein PG¹ is an arylsulfonyl protecting group such asbenzenesulfonyl, or preferably para-toluenesulfonyl (“tosyl”). Theprotecting group may be installed by reaction of the compound of formulaII with an arylsulfonyl chloride, preferably tosyl chloride, in thepresence of a base such as aqueous sodium hydroxide solution and anorganic solvent such as acetone. The reaction is typically run at 0° C.to about 50° C., preferably at about 23° C. (room temperature).Alternatively, bases such as sodium hydride and potassium tert-butoxidemay be used, employing a suitable solvent such as N,N-dimethylformamideor tetrahydrofuran. Several compounds of formula II are known in theliterature and have been prepared by the methods above. For example, thesynthesis of compound of formula II, wherein Q¹ is CI and R² and R³ arehydrogen has been reported previously, for example in WO 2007 012953.

In Scheme 1, Step 2, the protected compound of formula III is combinedwith 1-2 equivalents of an amine of formula IV in the presence of a 1-3equivalents of a base and a protic solvent to afford a compound offormula V. Suitable bases include triethylamine, diisopropylethylamine,and potassium carbonate while suitable solvents include methanol,ethanol, diisopropyl alcohol and water or mixtures thereof. The reactionis typically run at about 23° C. to about 150° C., preferably about 75°C. It will be noted that the amine of formula IV contains a second aminogroup that is protected with a protecting group PG² that can be removedunder conditions that do not lead to loss of PG¹. Suitable protectinggroups PG² include t-butoxycarbonyl (“Boc”) and (“Cbz”), preferablybenzyloxycarbonyl.

In Scheme 1, Step 3, the protecting group PG² is removed from thecompound of formula V under conditions that do not lead to loss of PG¹to give a primary amine (or a salt thereof) of formula VI. When PG² isbenzyloxycarbonyl, the benzyloxycarbonyl protecting group may be removedby hydrogenolysis wherein the compound of formula V is exposed tohydrogen or a hydrogen transfer reagent such as cyclohexene in thepresence of a hydrogenation catalyst such as palladium hydroxide using asolvent such as methanol, acetic acid or, preferably, ethanol.Alternatively, when PG² is benzyloxycarbonyl, the benzyloxycarbonylprotecting group may be removed by treatment of the compound of formulaV with a solution of hydrogen bromide (about 6 equivalents) in aceticacid optionally in the presence of a suitable solvent such as ethylacetate at a temperature from about minus 20° C. to about 40° C.,preferably less than 25° C. This latter deprotection method is preferredwherein n is 1, R², R³ and R⁴ are hydrogen, R¹ is methyl, PG¹ is tosyland PG² is benzyloxycarbonyl and provides the amine of formula VI as thedihydrobromide salt. When PG² is t-butoxycarbonyl, the t-butoxycarbonylprotecting group may be removed by treatment with an excess of an acidsuch as hydrochloric acid or trifluoroacetic acid in a solvent such asdichloromethane or 1,4-dioxane.

In Scheme 1, Step 4, the primary amine of formula VI (or salt thereof)is converted to a sulfonamide derivative of formula VII by treatmentwith an activated sulfonic acid derivative of formula VIII, wherein Q²is halogen, O-alkyl or O-aryl in the presence of a base. Most commonly,VIII is a sulfonyl chloride derivative wherein Q² is Cl. Many sulfonylchlorides may be obtained from commercial sources. Also, several methodsexist for the preparation of sulfonyl chlorides, which are well known tothose skilled in the art and have been described in texts such as“Advanced Organic Chemistry” by J. March, John Wiley & Sons (1985).Typically, the amine of formula VI is treated with a sulfonyl chloridederivative of formula VIII wherein Q² is CI in the presence of at leastone equivalent of a base such as triethylamine or diisopropylamine in asuitable solvent such as dichloromethane, tetrahydrofuran oracetonitrile. When a salt form of the amine is used, an additionalequivalent of base is used for each equivalent of acid forming the salt.For example, using a dihydrobromide salt, two extra equivalents of baseare used. The reaction may be run from about minus 20° C. to about 50°C., preferably starting the reaction at about 0° C. and then allowing itto warm to about 23° C. (room temperature).

Finally, in Scheme 1, Step 5, the sulfonamide derivative of formula VIIis de-protected to afford a compound of formula 1, wherein p is 2, X isNH, Y is AR⁵ and A is a bond. Two methods are typically employed, thechoice of which is determined by the compatibility of the conditionswith other functional groups on the molecule. The first method involvesexposure of the compound of formula VII to an excess (about 4equivalents) of a base such as lithium hydroxide or sodium hydroxide.The reaction is run in a solvent mixture containing water and an alcoholsuch as methanol or ethanol. It may also be run in a mixture of waterand tetrahydrofuran, and, optionally an alcohol such as methanol orethanol. The reaction may be run at a temperature of about 23° C. toabout 100° C., typically about 60° C. The second method, which ispreferred in instances where there is hydroxide-sensitive functionalitysuch as nitrile present in the molecule, involves reaction of thecompound of formula VII with an excess of tetrabutylammonium fluoride(4-25 equivalents) in a solvent such as 1,2-dimethoxyethane or,preferably tetrahydrofuran, The deprotection is conducted at atemperature of about 0° C. to about 60° C., preferably about 23° C.

Compounds of formula II, wherein Q¹ is halogen, are commerciallyavailable or are known in the chemical literature. For example,4-chloro-7H-pyrrolo[2,3-d]pyrimidine, wherein Q¹ is CI and R² and R³ areboth hydrogen, is a readily available commercial compound.

Compounds of formula IV are known in the chemical literature or may beprepared by standard chemical reactions well known to one skilled in theart.

An alternative method of preparing compounds of the invention wherein pis 2, X is NH, Y is AR⁵, A is a bond is shown in Scheme 2.

In Scheme 2, Step 1, a compound of formula IX is combined with abenzyloxycarbamate derivative of formula X in the presence of a base(1-5 equivalents) to provide a benzyloxycarbamate derivative of formulaXI. The reaction is carried out in a solvent such as water or an alcoholsuch as ethanol, optionally with addition of a miscible co-solvent suchas tetrahydrofuran. Suitable bases include potassium carbonate, cesiumcarbonate, triethylamine and diisopropylethylamine. The reaction is runat about 23° C. to about 100° C. When n is 1, R², R³ and R⁴ arehydrogen, and R¹ is methyl, the preferred conditions are to run thereaction in water, using potassium carbonate (3 equivalents) as base,starting the reaction at about 23° C. and then heating to about 95° C.

In Scheme 2, Step 2, the benzyloxycarbamate derivative of formula XI isde-protected by exposure to hydrogen or a hydrogen transfer reagent suchas cyclohexene in the presence of a hydrogenation catalyst such aspalladium hydroxide. At the same time, under the conditions of thedeprotection, the chlorine atom at the 2-position of7H-pyrrolo[2,3-d]pyrimidine ring is replaced with hydrogen to provide anamine hydrochloride salt of formula XII. The reaction is run in asolvent such as methanol or ethanol at a temperature of about 50° C. toabout 80° C. When R², R³ and R⁴ are hydrogen, and R¹ is methyl, thepreferred conditions are to run the reaction in ethanol at about 78° C.using palladium hydroxide as catalyst, and cyclohexene (about 20equivalents) as a hydrogen transfer reagent.

Finally, in Scheme 2, Step 3, the amine hydrochloride of formula XII isconverted to a sulfonamide of formula I, wherein p is 2, X is NH, Y isAR⁵, A is a bond by reaction with an activated sulfonic acid derivativeof formula VIII, wherein Q² is halogen, O-alkyl or O-aryl in thepresence of at least two equivalents of a base. Most commonly, VIII is asulfonyl chloride derivative wherein Q² is Cl. Suitable bases includetriethylamine, diisopropylethylamine and potassium carbonate. Suitablesolvents include N,N-dimethylformamide, and a mixture of tetrahydrofuranand water. The reaction may be run at a temperature of about minus 20°C. to about 50° C. preferably at about 23° C. Alternatively, the aminehydrochloride of formula XII is first treated with about 2 equivalentsof trimethylchlorosilane in the presence of about 2-3 equivalents of abase such as lithium bis(dimethylsilyl)amide or sodiumbis(dimethylsilyl)amide in an suitable aprotic solvent such astetrahydrofuran. Then, after about 1 hour, about 1.2 equivalents of thesulfonyl chloride of formula VIII, Q² is CI is added to provide, afterworkup, the sulfonamide of formula I, wherein p is 2, X is NH, Y is AR⁵,A is a bond The reaction may be run at a temperature of about minus 20°C. to about 50° C., preferably at about 23° C.

Compounds of formula IX, are commercially available or are known in thechemical literature. For example,2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine, wherein R² and R³ are bothhydrogen, is commercially available. Its synthesis is described in PCTInternational Publication No. WO2007/012953.

Sulfamides

Compounds of formula I, wherein p is 2, X is NH, and Y is NR_(a)R_(b),may be prepared according to Scheme 3.

In Scheme 3, Step 1, an amine of formula VI (or salt thereof), whereinPG¹ is an arylsulfonyl protecting group such benzenesulfonyl, orpreferably tosyl, is converted to oxazolidinone derivative of formulaXIII. First, a solution of N-chlorosulfonylisocyanate (1 equivalent) isslowly added to a solution of 2-bromoethanol (1 equivalent) at atemperature of about −40° C. to about 10° C., preferably about 0° C.Subsequently, after 0.5 to 2 hours, a solution of the amine of formulaVI (1 equivalent) and a base such as triethylamine ordiisopropylethylamine (about 3 equivalents, plus one equivalent for eachmole of acid forming a salt) is added slowly and the reaction is allowedto warm to about 23° C. over a period of about 10 to 24 hours. Suitablesolvents for the reaction include chloroform or preferablydichloromethane.

In Scheme 3, Step 2, the oxazolidinone derivative of formula XIII isreacted with 1-3 equivalents of an amine of the formula HNR_(a)R_(b), inthe presence of a base (2-5 equivalents), to afford a sulfamidederivative of formula XIV. Suitable bases include triethylamine anddiisopropylethylamine. The reaction is preferably carried out by heatingto about 90° C. to about 150° C. in a pressure vessel using a suitablesolvent such a N,N-dimethylformamide or acetonitrile.

In Scheme 3, Step 3, the compound of formula XIV is deprotected,removing the arylsulfonyl protecting group PG¹ to provide a sulfamidederivative of formula 1, wherein p is 2, X is NH, and Y is NR_(a)R_(b).The reaction may be carried out by one of the two general methodsdescribed for Scheme 1, Step 5. Again, the choice of deprotection methodis determined by the compatibility of the conditions with otherfunctional groups on the molecule. Alternatively, the sulfamides of theformula XIV may be obtained directly from an amine of formula VI (orsalt thereof). Thus, in Scheme 3, Step 4, the amine of formula VI (orsalt thereof) is treated with a sulfamoyl chloride of the formulaCl—SO₂NR_(a)R_(b) and a base such as triethylamine ordiisopropylethylamine as described for Scheme 1, Step 4. Sulfamoylchlorides of the formula Cl—SO₂NR_(a)R_(b) may be prepared, in turn,from amines of the formula HNR_(a)R_(b) according to the proceduresreviewed by W. R. Bowman and R. J. Marmon in “Comprehensive OrganicFunctional Group Transformations, Volume 2”, Pergamon (1995).

The compounds of formula I, wherein p is 2, X is NH, and Y isNR_(a)R_(b) may also be obtained directly from an amine of formula XII(or salt thereof). Thus, in Scheme 3, Step 5, the amine of formula XII(or salt thereof) is treated with a sulfamoyl chloride of the formulaCl—SO₂NR_(a)R_(b) and a base such as triethylamine ordiisopropylethylamine as described for Scheme 1, Step 4. Amines offormula XII are obtained as described for Scheme 2. Amines of formulaXII (or salts thereof) may be obtained by the removal of thearylsulfonyl protecting group PG¹ from a compound of the formula VI(refer to Scheme 1). The deprotection may be carried out by one of thetwo general deprotection methods described for Scheme 1, Step 5. Thechoice of deprotection method is determined by the compatibility of theconditions with other functional groups on the molecule.

Reverse Sulfonamides

Compounds of formula I, wherein p is 2, X is CH₂, and Y is NR_(a)R_(b),may be prepared according to Scheme 4.

In Scheme 4, Step 1, a compound of formula III (refer to Scheme 1), iscombined with an amino alcohol of formula XV in the presence of a baseand a polar solvent to afford a compound of formula XVI. Suitable basesinclude triethylamine and diisopropylethylamine while suitable solventsinclude methanol, diisopropyl alcohol and acetone. The reaction istypically run at about 23° C. to about 70° C. Preferably, a catalyticamount (about 1 mole %) of potassium iodide is added to the reaction.

In Scheme 4, Step 2, the compound of formula XVI is converted to acompound of formula XVII, wherein LG is a leaving group such as bromo,iodo, methanesulfonate or, preferably, para-toluenesulfonate. Methodsfor installing such leaving groups are well-known to those skilled inthe art and have been described in texts such as “Advanced OrganicChemistry” by J. March, John Wiley & Sons (1985). In the case where LGis para-toluenesulfonate, the compound of formula XVI is treated withpara-toluenesulfonyl chloride in the presence of a base such astriethylamine, diisopropylethylamine or N,N-dimethylaminopyridine in anaprotic solvent such as dichloromethane or tetrahydrofuran. The reactionis run at a temperature of about −10° C. to about 40° C., preferablybeginning at around 0° C. and allowing the reaction to warm to about 23°C.

In Scheme 4, Step 3, the compound of formula XVII is combined with asalt of thioacetic acid, preferably potassium thioacetate to yield athioester derivative of formula XVIII. The reaction is carried out in apolar solvent such as N,N-dimethylformamide or N-methylpyrrolidine, at atemperature of about 23° C. to about 80° C., preferably at about 55° C.

In Scheme 4, Step 4, the thioester derivative of formula XVIII isconverted to a sulfonic acid derivative of formula XIX by reaction withan aqueous solution of hydrogen peroxide, typically 30% by weight. Thereaction is carried out in an acidic solvent such as formic or aceticacid at a temperature from about 0° C. to about 40° C., preferably atabout 23° C.

In Scheme 4, Step 5, the sulfonic acid derivative of formula XIX isconverted to a sulfonyl chloride derivative of formula XX. Severalmethods for carrying out this functional group transformation are knownin the literature. The preferred method is to treat the compound offormula XIX with an excess (3-15 equivalents) of thionyl chloride in thepresence of a catalytic amount of N,N-dimethylformamide in an aproticsolvent such as dichloromethane or chloroform. The reaction may be runfrom about minus 20° C. to about 100° C., preferably beginning thereaction at about 0° C., and then warming to about 75° C.

Alternatively, in Scheme 4, Step 6, the thioester derivative of formulaXVIII may be directly converted to the sulfonyl chloride derivative offormula XX by treatment with a chlorinating agent. Several methods forcarrying out this functional group transformation are known in theliterature. Chlorinating agents include chlorine gas andN-chlorosuccinimide, and the reaction is commonly run in the presence ofan acid such as hydrochloric acid or acetic acid. Mixed aqueous solventssystems are often used, such as water and dichloromethane and water andacetonitrile.

In Scheme 4, Step 7, the sulfonyl chloride derivative of formula XX iscombined with 1-3 equivalents of an amine of the formula HNR_(a)R_(b) toform a sulfonamide derivative of formula XXI. The reaction is run in thepresence of at least one equivalent of a base such as triethylamine ordiiosopropylethylamine at a temperature from about minus 20° C. to about50° C., preferably starting the reaction at about 0° C. and allowing thereaction to warm to about 23° C. The reaction is run in an aproticsolvent such as tetrahydrofuran or dichloromethane.

Finally in Scheme 4, Step 8, the arylsulfonyl protecting group PG¹ isremoved to provide a compound of the formula I, wherein p is 2, X isCH₂, and Y is NR_(a)R_(b). The reaction may be carried out by one of thetwo general deprotection methods described for Scheme 1, Step 5. Thechoice of deprotection method is determined by the compatibility of theconditions with other functional groups on the molecule. Amino alcoholsof formula XV are known in the chemical literature or may be prepared bymethods well known to one skilled in the art.

Sulfones, Sulfoxides and Thioethers

Compounds of formula I, wherein p is 0, 1, or 2, X is CH₂, Y is AR⁵ andA is a bond, may be prepared according to Scheme 5.

In Scheme 5, Step 1, a compound of formula XVII (refer to Scheme 4) istreated with 1-2 equivalents of a thiol of the formula R⁵SH in thepresence of 1-2 equivalents of a base to give a sulfide of the formulaXXIII. Suitable bases include sodium hydride, sodiumbis(trimethylsilyl)amide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) andpreferably, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction iscarried out in a solvent such as N,N-dimethylformamide orN-methylpyrrolidinone at a temperature from about 0° C. to about 50° C.,preferably at about 23° C.

In Scheme 5, Step 2, the compound of formula XXIII is deprotected,removing the arylsulfonyl protecting group PG¹ to provide a compound offormula XXIV. The reaction may be carried out by one of the two generaldeprotection methods described for Scheme 1, Step 5. The choice ofdeprotection method is determined by the compatibility of the conditionswith other functional groups on the molecule.

In Scheme 5, Step 3, a sulfide of formula XXIV is oxidized to yield asulfone of formula I, wherein p is 2, X is CH₂, Y is AR⁵ and A is abond. Several methods are known in the literature and all involve theuse of an oxidant such as metachloroperbenzoic acid, hydrogen peroxide,or potassium peroxymonosulfate (Oxone®). A preferred method is to treatthe compound of formula XXIV with 2 equivalents of potassiumperoxymonosulfate (Oxone®) in a solvent mixture of tetrahydrofuran,ethanol and water at a temperature of about 23° C. The sulfide offormula XXIV may also be oxidized under milder conditions, for exampleusing 1 equivalent of meta-chlorobenzoic acid in a solvent such asdichloromethane at about 0° C. to produce a sulfoxide of formula I,wherein p is 1, X is CH₂, Y is AR⁵ and A is a bond

It is noted that the order of Steps 2 and 3 in Scheme 5, may optionallybe reversed such that the oxidation step is carried out prior to thedeprotection step.

Compounds of the formula I, wherein p is 0, X is CH₂, Y is AR⁵ and A isa bond are prepared in Scheme 5, Step 4 by removing the arylsulfonylprotecting group PG¹ from a compound of formula XXIII. The reaction maybe carried out by one of the two general deprotection methods describedfor Scheme 1, Step 5. Again, the choice of deprotection method isdetermined by the compatibility of the conditions with other functionalgroups on the molecule.

In Scheme 5, Step 5, compounds of the formula XXIII are alternativelyprepared from a thioacetate derivative of formula XVIII. First, thethioacetate of formula XVIII is dissolved in a solvent such as ethanol,methanol, or water (or a mixture thereof). A suitable base such aspotassium carbonate or cesium carbonate (about 2 equivalents) is addedand nitrogen is bubbled through the solution to remove oxygen. Analkylating agent of the formula R⁵-LG is then added, wherein LG is aleaving group such as bromo, iodo, methanesulfonate or,para-toluene-sulfonate. The reaction is conducted at a temperature fromabout minus 20° C. to about 30° C. Preferably, the reaction is startedat about 0° C. and then allowed to warm to about 23° C.

Many thiols of the formula R⁵SH and alkylating agents of the formulaR⁵-LG may be obtained from commercial sources. Also, several methodsexist for the preparation of such compounds, which are well known tothose skilled in the art and have been described in texts such as“Advanced Organic Chemistry” by J. March, John Wiley & Sons (1985).

It is noted that certain compounds of the invention can be obtained byfunctional group transformations at a late stage of the synthesis, forexample, by chemical modification of the groups R⁴ or R⁵ after carryingout Steps 4 or 5 in Scheme 1, Step 3 in Scheme 2, Steps 2, 3 or 4 inScheme 3, Steps 7 or 8 Scheme 4 and Steps 2, 3, 4 or 5 in Scheme 5. Suchfunctional group transformations may include one step or multiple steps,for example, reduction of an ester to an alcohol, reoxidation to analdehyde, addition of an organomagesium reagent to form a secondaryalcohol, reoxidation to a ketone and, finally, addition of anorganomagesium reagent to yield a tertiary alcohol.

In executing the synthesis of the compounds of the invention, oneskilled in the art will recognize the need to sample and assay reactionmixtures prior to work up in order to monitor the progress of reactionsand decide whether the reaction should be continued or whether it isready to be worked up to obtain the desired product. Common methods forassaying reaction mixtures include thin-layer chromatography (TLC),liquid chromatography/mass spectroscopy (LCMS), and nuclear magneticresonance (NMR).

One skilled in the art will also recognize that the compounds of theinvention may be prepared as mixtures of diastereomers or geometricisomers (e.g., cis and trans substitution on a cycloalkane ring). Theseisomers can be separated by standard chromatographic techniques, such asnormal phase chromatography on silica gel, reverse phase preparativehigh pressure liquid chromatography or supercritical fluidchromatography. One skilled in the art will also recognize that somecompounds of the invention are chiral and thus may be prepared asracemic or scalemic mixtures of enantiomers. Several methods areavailable and are well known to those skilled in the art for theseparation of enantiomers. A preferred method for the routine separationenantiomers is supercritical fluid chromatography employing a chiralstationary phase.

Experimental Section

Except where otherwise noted, reactions were run under an atmosphere ofnitrogen. Chromatography on silica gel was carried out using 250-400mesh silica gel using pressurized nitrogen (˜10-15 psi) to drive solventthrough the column (“flash chromatography”). Where indicated, solutionsand reaction mixtures were concentrated by rotary evaporation undervacuum.

Example 12,2,2-Trifluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}ethanesulfonamideStep 1: Benzyl [cis-3-(methylamino)cyclobutyl]carbamate and benzyl[trans-3-(methylamino)cyclobutyl]carbamate

A 33% solution of methylamine (1000 mL, 9.13 mol) in absolute ethanolwas added to a mixture of benzyl (3-oxocyclobutyl)carbamate(WO2012/75381 A1 and WO2012/09678 A1) (200 g, 0.913 mol) and acetic acid(88 mL) stirring in ethanol (1000 mL) at 0° C. The reaction mixturestirred for at 0° C. for 1.5 hours and then stirred at room temperaturefor 2 hours. Lithium borohydride (41 g, 2.05 mol) was added in portionsto the reaction mixture at −70° C. After addition was complete, thereaction mixture was stirred at −70° C. for 1 hour and then allowed towarm to room temperature over 12 hours. The reaction mixture wasquenched with water (400 mL), and concentrated under vacuum to removeethanol. The aqueous layer was acidified with concentrated hydrochloricacid to pH 2, washed with ethyl acetate (2×1000 mL), basified with 10%sodium hydroxide to pH 9-10 and then extracted with dichloromethane(3×1000 mL). The combined organic layers were washed with brine (1000mL), dried over sodium sulfate, and concentrated to obtain the crudeproduct as a pale brown liquid. This was dissolved in dichloromethane(400 mL) and cooled to 0° C. To the resulting solution was added asolution of 4M HCl in dioxane (300 mL). The mixture was stirred at 0° C.for 30 minutes, and then at room temperature for 12 hours. The reactionmixture was filtered and the remaining solid was recrystallized from amixture of methanol and methyl tert-butyl ether to afford the cis-isomeras a white solid (111.09 g, 52%). ¹H NMR: (400 MHz, D₂O): δ 7.33-7.38(m, 5H); 5.02 (s, 2H), 3.83-3.87 (m, 1H), 3.89-3.41 (m, 1H), 2.66-2.70(m, 2H), 2.56 (s, 3H), 2.03-2.05 (m, 2H). LC/MS (exact mass) calculatedfor C₁₃H₁₈N₂O₂; 234.137. found (M+H⁺); 235.1.

The trans isomer was isolated from the mother liquor using supercriticalfluid chromatography.

Step 2: Benzyl{cis-3-[(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino]-cyclobutyl}carbamate

To a solution of potassium carbonate (20.47 g, 148 mmol) in water (180mL) was added benzyl [cis-3-(methylamino)cyclobutyl]carbamate (13.57 g,50.2 mmol), followed by 2,4-dichloro-7H-pyrrolo(2,3-d)pyrimidine (9.0 g,47.9 mmol) at room temperature. After addition was complete, thereaction mixture was stirred at 95° C. overnight. The mixture wasfiltered to collect the solid. The filter cake was washed with water anddried under vacuum to afford the title compound (16.5 g, 89.7%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.81 (sm 1H), 7.65 (d, 1H),7.38 (m, 5H), 7.16 (m, 1H), 6.67 (d, 1H), 5.02 (s, 2H), 4.81 (m, 1H),3.85 (m, 1H), 3.25 (s, 3H), 2.53 (m, 2H), 2.25 (m, 2H). LC/MS (exactmass) calculated for C₁₉H₂₀CIN₅O₂; 385.131. found (M+H⁺); 386.1.

Step 3:cis-N-Methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride

A mixture of{cis-3-[(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)-amino]cyclobutyl}carbamate(13.0 g, 34.0 mmol), Pd(OH)₂ (40.3 g, 40.8 mmol) and cyclohexene (72.5mL, 0.71 mol) in ethanol (300 mL) was stirred at reflux for 3 hours. Thereaction mixture was filtered through a pad of Celite® and the pad waswashed with methanol. The filtrate was concentrated under vacuum toafford the title compound (4.8 g, 66%) as a white solid. ¹H NMR (400MHz, DMSO-d₆): δ 11.68 (br, 1H), 8.11 (s, 1H), 7.67 (br, 2H), 7.17 (d,1H), 6.65 (d, 1H), 5.08 (m, 1H), 3.45 (m, 1H), 3.26 (s, 3H), 2.31 (m,4H). LC/MS (exact mass) calculated for C₁₁H₁₅N₅; 217.133. found (M+H⁺);218.1.

Step 4:2,2,2-Trifluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}ethanesulfonamide

To a solution ofcis-N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride (100 mg, 0.39 mmol) in tetrahydrofuran (0.8 mL) was addedlithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran) (0.9mL, 0.9 mmol) and chlorotrimethylsilane (94 mg, 0.88 mmol) at roomtemperature. The reaction mixture was stirred for 45 minutes and then2,2,2-trifluoroethanesulfonyl chloride (86 mg, 0.47 mmol) was addedslowly. The mixture was stirred at room temperature for 18 hours andthen partitioned between dichloromethane and water. The aqueous layerwas and extracted twice with dichloromethane and the combined organiclayers were concentrated to afford the crude product as a tan solid. Thecrude material was purified by chromatography on silica gel eluting witha mixture of dichloromethane and methanol (93:7) to afford the titlecompound as a white solid (93 mg, 65%). ¹H NMR (400 MHz, DMSO-d₆): δ11.61 (br. s., 1H), 8.20 (d, 1H), 8.08 (s, 1H), 7.13 (d, 1H), 6.60 (d,1H), 4.80-4.94 (m, 1H), 4.34 (q, 2H), 3.58-3.71 (m, 1H), 3.23 (s, 3H),2.55-2.67 (m, 2H), 2.17-2.30 (m, 2H). LC/MS (exact mass) calculated forC₁₃H₁₆F₃N₆O₂S; 363.098. found (M+H⁺); 363.9.

The following compounds, Examples 2-7, were prepared fromcis-N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride (Example 1, Step 3) in a similar manner to that describedin Example 1, Step 4, substituting the indicated sulfonyl chloride for2,2,2-trifluoroethanesulfonyl chloride.

Example 2N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]cyclobutyl}-propane-1-sulfonamide

This compound was prepared using 1-propanesulfonyl chloride. The crudecompound was purified by chromatography on silica gel eluting with amixture of dichloromethane and methanol (93:7) to afford the titlecompound as a tan solid (78% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.60(br s, 1H), 8.08 (s, 1H), 7.46 (d, 1H), 7.12 (d, 1H), 6.61 (d, 1H),4.81-4.94 (m, 1H), 3.47-3.62 (m, 1H), 3.23 (s, 3H), 2.87-2.96 (m, 2 H),2.52-2.63 (m, 2H), 2.14-2.27 (m, 2H) 1.60-1.73 (m, 2H) 0.96 (t, 3H).LC/MS (exact mass) calculated for C₁₄H₂₁N₅O₂S; 323.142. found (M+H⁺);324.1.

Example 32-Methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}propane-1-sulfonamide

This compound was prepared using 2-methyl-1 propanesulfonyl chloride.The crude compound was purified by chromatography on silica gel elutingwith a mixture of dichloromethane and methanol (93:7) to afford thetitle compound as a white solid (52%). ¹H NMR (400 MHz, DMSO-d₆): δ11.64 (br s, 1H), 8.12 (s, 1H), 7.51 (d, 1H), 7.03-7.26 (m, 1H), 6.65(d, 1H), 4.82-5.02 (m, 1H), 3.52-3.70 (m, 1H), 3.26 (s, 3H), 2.87 (d,2H), 2.55-2.67 (m, 2H), 2.18-2.30 (m, 2H), 2.11 (dt, 1H), 1.04 (d, 6H).LC/MS (exact mass) calculated for C₁₅H₂₃N₅O₂S; 337.157. found (M+H⁺);338.0.

Example 4A and Example 4B cis- andtrans-3-(Cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}cyclobutanesulfonamide

These compounds were prepared using a mixture (˜1:1) of cis- andtrans-3-(cyanomethyl)cyclobutanesulfonyl chloride. The crude mixture ofcis and trans isomers was purified by chromatography on silica geleluting with a gradient of dichloromethane and methanol (100:0 to 10:1)to afford a mixture (420 mg) of the title compounds as a white solid(67%). The cis and trans isomers were separated by supercritical fluidchromatography.

cis-isomer 4A: 160 mg (21%). ¹H NMR (400 MHz, methanol-d₄): δ 8.12 (s,1H), 7.13-7.12 (d, 1H), 6.69-6.69 (d, 1H), 4.92-4.89 (m, 1H), 3.84-3.78(m, 1H), 3.76-3.67 (m, 1H), 3.36 (s, 3H), 2.79-2.73 (m, 2H), 2.65-2.64(m, 3H), 2.58-2.52 (m, 2H), 2.32-2.19 (m, 4H). LC/MS (exact mass)calculated for C₁₇H₂₂N₆O₂S; 374.152. found (M+H⁺); 375.3.

trans-isomer 4B: 155 mg (20%). ¹H NMR (400 MHz, methanol-d₄): δ 8.13 (s,1H), 7.13 (d, 1H), 6.70 (d, 1H), 4.94-4.89 (m, 1H), 3.89-3.85 (m, 1H),3.72-3.69 (m, 1H), 3.36 (s, 3H), 2.85-2.62 (m, 7H), 2.31-2.23 (m, 4H).LC/MS (exact mass) calculated for C₁₇H₂₂N₆O₂S; 374.152. found (M+H⁺);374.9.

The mixture of cis- and trans-3-(cyanomethyl)cyclobutanesulfonylchlorides was prepared as follows:

Step 1: [3-(Benzyloxy)cyclobutylidene]acetonitrile

To a cold suspension of sodium hydride (125 mg, 3.12 mmol) intetrahydrofuran (12 mL) at 0° C. was added diethylcyanomethylphosphonate (1.21 g, 3.40 mmol). The mixture was stirred atroom temperature for 1 hour before adding a solution of3-(benzyloxy)cyclobutanone (500 mg, 2.84 mmol) in tetrahydrofuran (8mL). The mixture was stirred at room temperature overnight, and was thenquenched with water. The mixture was extracted with ethyl acetate (3×25mL) and the combined organic layers were dried over sodium sulfate andconcentrated. The residue was chromatographed on silica gel eluting witha gradient of petroleum ether and ethyl acetate (100:0 to 85:15) toafford the title compound (450 mg, 80%) as a yellow oil.

Step 2: [3-(Benzyloxy)cyclobutyl]acetonitrile

A mixture of [3-(benzyloxy)cyclobutylidene]acetonitrile (10.2 g, 51mmol) and 10% Pd/C (2.0 g) in dry tetrahydrofuran was pressurized to 50psi with hydrogen and stirred at room temperature for 3 days. Themixture was then filtered and concentrated under vacuum. The residue waschromatographed on silica gel eluting with a gradient of petroleum etherand ethyl acetate (100:0 to 80:20) to give the title compound (7 g, 70%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.36-7.28 (m, 5H),4.44-4.43 (m, 2H), 4.30-4.09 (m, 1H), 3.98-3.95 (m, 1H), 2.64-2.45 (m,4H), 1.81-1.759 (m, 2H).

Step 3: (3-Hydroxycyclobutyl)acetonitrile

To a solution of [3-(benzyloxy)cyclobutyl]acetonitrile (1 g, 5.00 mmol)in acetonitrite (15 mL) was added dropwise iodotrimethylsilane (1.5 g,7.50 mmol) at 0° C. The mixture was stirred at room temperatureovernight. The mixture was quenched with triethylamine, concentrated andthen purified by chromatography on silica gel eluting with a gradient ofpetroleum ether and ethyl acetate (1:0 to 1:1) to afford the titlecompound (340 mg, 62%) as yellow oil. ¹H NMR (400 MHz, CDCl₃): δ4.55-4.15 (m, 1H), 2.49-2.46 (m, 2H), 2.25-2.21 (m, 2H), 2.14-2.08 (m,1H), 1.79-1.72 (m, 2H).

Step 4: 3-(Cyanomethyl)cyclobutyl-4-methylbenzenesulfonate

To a solution of (3-hydroxycyclobutyl)acetonitrile (333 mg, 3.0 mmol) indry dichloromethane (25 mL) was added 4-dimethylaminopyridine (732 mg,6.0 mmol). The mixture stirred at room temperature for 5 minutes andthen p-toluenesulfonyl chloride (859 mg, 4.5 mmol) was added. Theresulting mixture was stirred at room temperature overnight. The mixturewas washed with water (2×15 mL). The organic layer was dried over sodiumsulfate and concentrated. The residue was purified by chromatography onsilica gel eluting with a gradient of petroleum ether and ethyl acetate(10:0 to 7:3) to afford the title compound (520 mg, 65% yield) ascolorless oil.

Step 5: S-[3-(Cyanomethyl)cyclobutyl]ethanethioate

The mixture of 3-(cyanomethyl)cyclobutyl 4-methylbenzenesulfonate (1.5g, 5.7 mmol) and potassium thioacetate (1.29 g, 3.00 mmol) inN,N-dimethylformamide (8 mL) was heated at 80° C. overnight. The mixturewas diluted with ethyl acetate (15 mL), washed with water (30 mL) andbrine (2×30 mL), dried over sodium sulfate and concentrated. The residuewas purified by preparative thin layer chromatography eluting with amixture of petroleum ether and ethyl acetate (3:1) to afford the titlecompound (750 mg, 78%) as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ4.12-3.92 (m, 1H), 2.86-2.77 (m, 2H), 2.71-2.47 (m, 2H), 2.42-2.37 (m,2H), 2.30-2.29 (m, 3H), 1.97-1.90 (m, 1H).

Step 6: 3-(Cyanomethyl)cyclobutanesulfonyl chloride

A mixture of N-chlorosuccinimide (1.6 g, 12.0 mmol) in concentrated HCl(3 mL) and acetonitrile (12 mL) was stirred at room temperature for 10minutes. S-[3-(cyanomethyl)cyclobutyl]ethanethioate (507 mg, 3.0 mmol)in acetonitrile (3 mL) was added at 0° C. and stirred for 10 minutes.The mixture was diluted with aqueous sodium bicarbonate (50 mL), andextracted with methyl tert-butyl ether (3×50 mL). The combined driedorganic layers were dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by chromatography on silicagel eluting with a mixture of petroleum ether and ethyl acetate (100:0to 50:50) to afford the title compound (400 mg, 69%) as a yellow oil. ¹HNMR (400 MHz, CDCl₃): δ 4.45-4.40 (m, 1H), 3.06-2.71 (m, 3H), 2.61-2.49(m, 4H).

Example 51-[3-(Cyanomethyl)oxetan-3-yl]-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methanesulfonamide

This compound was prepared from[3-(cyanomethyl)oxetan-3-yl]methanesulfonyl chloride. The crude compoundwas purified using preparative thin layer chromatography eluting withethyl acetate to afford the title compound as a white solid (32%). ¹HNMR (400 MHz, methanol-d₄): δ 8.13 (s, 1H), 7.14-7.13 (m, 1H), 6.71-6.70(m, 1H), 5.06-5.05 (m, 1H), 4.85-4.81 (m, 2H), 4.52-4.50 (m, 2H),3.77-3.75 (m, 1H), 3.63 (m, 2H), 3.39 (s, 3H), 3.29-3.26 (m, 2H),2.85-2.78 (m, 2H), 2.38-2.30 (m, 2H). LC/MS (exact mass) calculated forC₁₇H₂₂N₆O₃S; 390.147. found (M+H⁺); 391.0.

[3-(Cyanomethyl)oxetan-3-yl]methanesulfonyl chloride Step 1:[3-(Cyanomethyl)oxetan-3-yl]methyl 4-methylbenzenesulfonate

This compound was prepared following the procedure of Example 4 Step 4,substituting [3-(Hydroxymethyl)-3-oxetanyl]acetonitrile for(3-hydroxycyclobutyl)acetonitrile. The crude compound was purified bychromatography on silica gel eluting with a mixture of petroleum etherand ethyl acetate (1:0 to 1:1) to afford the title compound as a whitesolid (10%). ¹H NMR (400 MHz, CDCl₃): δ 7.82-7.80 (m, 2H), 7.41-7.39 (m,2H), 4.54-4.35 (m, 4H), 4.31 (s, 2H), 2.79 (s, 2H), 2.45 (s, 3H).

Step 2: [3-(Cyanomethyl)oxetan-3-yl]methyl thiocyanate

A solution of [3-(cyanomethyl)oxetan-3-yl]methyl4-methylbenzenesulfonate (150 mg, 0.53 mmol) and potassium thiocyanate(104 mg, 1.07 mmol) was stirred in ethanol (10 mL). The reaction washeated to 85° C. and stirred for 16 hours. The solvent was evaporated toafford the crude title compound as a white solid.

Step 3: [3-(Cyanomethyl)oxetan-3-yl]methanesulfonyl chloride

Chlorine gas was bubbled through a solution of[3-(cyanomethyl)oxetan-3-yl]methyl thiocyanate (0.53 mmol, crude) inwater (10 mL) at 0° C. for 30 minutes. The reaction mixture wasextracted with methyl tert-butyl ether (2×20 mL). The combined organiclayers were dried over sodium sulfate and concentrated to afford thetitle compound (20 mg, 18%).

Example 6N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1-oxetan-3-ylmethanesulfonamide

This compound was prepared using oxetan-3-ylmethanesulfonyl chloride.The crude compound was purified by chromatography on silica gel elutingwith a mixture of dichloromethane and methanol (85:15) to afford thetitle compound as a white solid (23%). ¹H NMR (400 MHz, methanol-d₄): δ8.13 (m, 1H), 7.13 (d, J=4 Hz, 1H), 6.70-6.69 (m, J=4 Hz, 1H), 4.93-4.91(m, 1H), 4.84-4.83 (m, 2H), 4.63-4.59 (m, 2H), 3.74-3.68 (m, 1H),3.58-3.56 (m, 1H), 3.47-3.45 (m, 2H), 3.37 (s, 3H), 2.79-2.77 (m, 2H),2.32-2.29 (m, 2H). LC/MS (exact mass) calculated for C₁₅H₂₁NSO₃S;351.136. found (M+H⁺); 352.1.

Oxetan-3-ylmethanesulfonyl chloride Step 1: Oxetan-3-ylmethylthiocyanate

This compound was prepared according to the procedure of Example 5, Step2, substituting oxetan-3-ylmethyl 4-methylbenzenesulfonate(WO2012/117000A1) for [3-(cyanomethyl)oxetan-3-yl]methyl4-methylbenzenesulfonate to afford the crude title compound as a whitesolid. (100%).

Step 2: Oxetan-3-ylmethanesulfonyl chloride

This compound was prepared in crude form (25% yield) following theprocedure of Example 5 Step 3, substituting oxetan-3-ylmethylthiocyanate for [3-(cyanomethyl)oxetan-3-yl]methyl thiocyanate.

Example 7A and 7B cis- andtrans-3-(Cyanomethyl)-3-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}cyclobutanesulfonamide

These compounds were prepared using a mixture (˜1:1) of cis- andtrans-3-(cyanomethyl)-3-methylcyclobutanesulfonyl chloride. The crudemixture of cis- and trans isomers was purified by chromatography onsilica gel eluting with a gradient of petroleum ether:ethyl acetate(10:1 to 1:15) to afford a mixture (70 mg) of the title compounds as alight brown solid (28%). The cis and trans isomers were then separatedby supercritical fluid chromatography (SFC).

cis-isomer (7A): 26 mg (10%); SFC retention time=7.11 minutes; ¹H NMR(400 MHz, methanol-d₄): δ 8.13 (s, 1H), 7.13-7.13 (d, 1H), 6.69 (d, 1H),4.93-4.86 (m, 1H), 3.91-3.87 (m, 1H), 3.71-3.65 (m, 1H), 3.37-3.33 (m,3H), 2.77-2.75 (m, 2H), 2.68 (s, 2H), 2.41-2.36 (m, 2H), 2.26-2.21 (m,2H), 1.34 (m, 3H). LC/MS (exact mass) calculated for C₁₈H₂₄N₆O₂S;388.168. found (M+H⁺); 389.1.

trans-isomer (7B) 24 mg (10%); SFC retention time=11.35 minutes; ¹H NMR(400 MHz, methanol-d₄): δ 8.13 (s, 1H), 7.14 (d, 1H), 6.69 (d, 1H),4.93-4.86 (m, 1H), 3.96-3.86 (m, 1H), 3.72-3.65 (m, 1H), 3.36-3.31 (m,3H), 2.77-2.75 (m, 2H), 2.71 (s, 2H), 2.34-2.26 (m, 6H), 1.33 (m, 3H).LC/MS (exact mass) calculated for C₁₈H₂₄N₆O₂S; 388.168. found (M+H⁺);389.0.

The mixture of cis- andtrans-3-(cyanomethyl)-3-methylcyclobutanesulfonyl chlorides was preparedas follows:

Step 1: 1-Methyl-3-methylenecyclobutanecarbonitrile

To a solution of 3-methylenecyclobutanecarbonitrile (35.0 g, 373.0 mmol)in tetrahydrofuran (200 mL) was added dropwise lithiumbis(trimethylsilyl)amide (450 mL, 1 M) at −78° C. The solution wasstirred for 1 hour at −78° C. and iodomethane (30 mL, 448 mmol) wasadded to the reaction. After 1 hour, the mixture was warmed to roomtemperature and stirred overnight. The reaction mixture was quenchedwith aqueous ammonium chloride (380 mL) and extracted with methyltert-butyl ether (3×400 mL). The combined organic layers were dried oversodium sulfate and concentrated. The crude product was purified bydistillation under reduced pressure to afford the title compound (20 g,50%) as clear oil. ¹H NMR (400 MHz, CDCl₃): δ 4.90-4.89 (m, 2H),3.24-3.20 (m, 2H), 2.67-2.62 (m, 2H), 1.50 (s, 3H).

Step 2: 1-Methyl-3-methylenecyclobutanecarboxylic acid

To a solution of 1-methyl-3-methylenecyclobutanecarbonitrile (10.0 g,93.3 mmol) in water (50 mL) and ethanol (50 mL) was added potassiumhydroxide (25.6 g, 466.6 mmol). The reaction mixture was heated toreflux and stirred overnight. The ethanol was removed under reducedpressure, and the solution was cooled to below 10° C., acidified withconcentrated hydrochloric acid to pH 1. The aqueous phase was extractedwith ethyl acetate (3×150 mL). The combined organic layers were driedover sodium sulfate and concentrated to afford the title compound (9 g,77%). ¹H NMR (400 MHz, CDCl₃): δ 11.90 (s, 1H), 4.88-4.85 (m, 2H),3.23-3.17 (m, 2H), 2.53-2.41 (m, 2H), 1.45 (s, 3H).

Step 3: Ethyl 1-methyl-3-methylenecyclobutanecarboxylate

To a solution of 1-methyl-3-methylenecyclobutanecarboxylic acid (6 g,47.6 mmol) in dichloromethane (30 mL) at 0° C. was added dropwisethionyl chloride (11.0 mL, 143 mmol). The solution was stirred at 0° C.for 1 hour. Three drops of N,N-dimethylformamide were added to thesolution. The solution was stirred at 0° C. for 30 minutes. The solventwas evaporated and dichloromethane (20 mL) and ethanol (125 mL) wereadded to the residue. The resulting solution was stirred for 16 hours atroom temperature. The solvent was evaporated and water (20 mL) was addedto the residue. The aqueous layer was extracted with dichloromethane(4×20 mL). The combined organic layers were dried over sodium sulfateand concentrated. The crude product was purified by chromatography onsilica gel eluting with a gradient of petroleum ether and ethyl acetate(20:1 to 10:1) to afford the title compound (5 g, 68%). ¹H NMR (400 MHz,CDCl₃): δ 4.85-4.83 (m, 2H), 4.17-4.12 (m, 2H), 3.18-3.12 (m, 2H),2.48-2.42 (m, 2H), 1.41 (s, 3H), 1.27-1.23 (m, 3H).

Step 4: (1-Methyl-3-methylenecyclobutyl)methanol

A mixture of ethyl 1-methyl-3-methylenecyclobutanecarboxylate (4.55 g,29.5 mmol) lithium aluminum hydride (2.8 g, 72 mmol) in tetrahydrofuran(50 mL) was stirred overnight at room temperature. To the reactionmixture was added Na₂SO₄.10H₂O (3.7 g, 11.5 mmol) and the resultingmixture was stirred for 1 hour at room temperature. The solids wereremoved by filtration and the filtrate was concentrated under vacuum.The residue was extracted with dichloromethane (3×50 mL). The combinedorganic extracts were dried over sodium sulfate and concentrated toafford the title compound (2.6 g, 79%) as a colorless oil. ¹H NMR (400MHz, CDCl₃): δ 4.79-4.78 (m, 2H), 3.48 (s, 2H), 2.53-2.48 (m, 2H),2.36-2.27 (m, 2H), 1.16 (s, 3H).

Step 5: (1-Methyl-3-methylenecyclobutyl)methyl 4-methylbenzenesulfonate

This compound was prepared following Example 4, Step 4, substituting(1-methyl-3-methylenecyclobutyl)methanol for(3-hydroxycyclobutyl)acetonitrile. The crude compound was purified bychromatography on silica gel eluting with a gradient of petroleum etherand ethyl acetate (20:1 to 4:1) to afford the title compound (70%). ¹HNMR (400 MHz, CDCl₃): δ 7.79 (d, 2H), 7.34 (d, 2H), 4.79-4.78 (m, 2H),3.90 (s, 2H), 2.51-2.47 (m, 2H), 2.44 (s, 3H), 2.35-2.31 (m, 2H), 1.15(s, 3H).

Step 6: (1-Methyl-3-methylenecyclobutyl)acetonitrile

A mixture of (1-methyl-3-methylenecyclobutyl)methyl4-methylbenzenesulfonate (2.5 g, 9.4 mmol), potassium cyanide (1.3 g, 19mmol) and N,N-dimethylformamide (8 mL) was stirred overnight at 70° C.Water (10 mL) and methyl tert-butyl ether (20 mL) were added to themixture and the organic layer was separated. The aqueous phase wasextracted with methyl tert-butyl ether (3×30 mL). The combined organiclayers were washed with an aqueous saturated sodium bicarbonate solution(15 mL), dried over sodium sulfate, and concentrated. The crude productwas purified by chromatography on silica gel eluting with a gradient ofpetroleum ether and ethyl acetate (10:1 to 5:1) to afford the titlecompound (1.1 g, 97%) as light brown oil. ¹H NMR (400 MHz, CDCl₃): δ4.88-4.87 (m, 2H), 2.62-2.54 (m, 2H), 2.50 (s, 2H), 1.33 (s, 3H).

Step 7: (1-Methyl-3-oxocyclobutyl)acetonitrile

Ozone gas was bubbled through a solution of(1-methyl-3-methylenecyclo-butyl)acetonitrile (1.08 g, 8.91 mmol) indichloromethane (30 mL) −78° C. for 10 minutes. After purging thesolution with nitrogen gas, dimethylsulfide (10 mL) was added dropwiseto the solution at −78° C. The solution was stirred for 30 minutes at−78° C. and the solvent was removed under reduced pressure. The crudeproduct was purified by chromatography on silica gel eluting with agradient of petroleum ether and ethyl acetate (20:1 to 8:1) to affordthe title compound (920 mg, 84%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃): δ 3.11-3.06 (m, 2H), 2.96-2.91 (m, 2H), 2.69 (s, 2H), 1.53 (s,3H).

Step 8: (3-Hydroxy-1-methylcyclobutyl)acetonitrile

To a solution of (1-methyl-3-oxocyclobutyl)acetonitrile (400 mg, 3.25mmol) in tetrahydrofuran (15 mL) was added sodium borohydride (246 mg,6.5 mmol). The mixture was stirred for 3 hours at room temperature.Acetone (2 mL) was added and then the solvent was evaporated. Water (10mL) was added to the residue and the aqueous phase was extracted withdichloromethane (4×15 mL). The combined organic layers were dried oversodium sulfate and concentrated. The crude product was purified bychromatography on silica gel eluting with a gradient of petroleum etherand ethyl acetate (10:1 to 1:1) to afford the title compound (300 mg,74%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 4.38-4.34 (m, 2H),2.46-2.27 (m, 4H), 1.94-1.86 (m, 2H), 1.33-1.12 (m, 3H).

Step 9: 3-(Cyanomethyl)-3-methylcyclobutyl 4-methylbenzenesulfonate

This compound was prepared following Example 7, Step 5, substituting(3-hydroxy-1-methylcyclobutyl)acetonitrile for(1-methyl-3-methylenecyclo-butyl)methanol. The crude compound waspurified by chromatography on silica gel eluting with a gradient ofpetroleum ether and ethyl acetate (20:1 to 4:1) to afford the titlecompound (36%). ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, 2H), 7.35 (d, 2H),4.89-4.81 (m, 1H), 2.45 (s, 3H), 2.43-2.34 (m, 3H), 2.26-2.21 (m, 1H),2.15-2.11 (m, 2H), 1.33 (s, 3H).

Step 10: S-[3-(Cyanomethyl)-3-methylcyclobutyl]ethanethioate

This compound was prepared in 89% yield (crude) following the procedureof Example 4, Step 5, substituting 3-(cyanomethyl)-3-methylcyclobutyl4-methylbenzenesulfonate for 3-(cyanomethyl)cyclobutyl4-methylbenzene-sulfonate. ¹H NMR (400 MHz, CDCl₃): δ 3.12 (s, 1H),2.46-2.30 (m, 4H), 2.19 (s, 2H), 1.29 (s, 1H) 1.26-1.24 (m, 1H),1.18-1.14 (m, 1H), 1.13 (s, 3H).

Step 11: 3-(Cyanomethyl)-3-methylcyclobutanesulfonyl chloride

This compound was prepared following Example 4 Step 6, substitutingS-[3-(cyanomethyl)-3-methylcyclobutyl]ethanethioate forS-[3-(cyanomethyl)-cyclobutyl]ethanethioate. The crude compound waspurified using chromatography on silica gel eluting with a gradient ofpetroleum ether and ethyl acetate (90:10 to 30:70) to afford the titlecompound as a yellow liquid (66%). ¹H NMR (400 MHz, CDCl₃): δ 4.45-4.38(m, 1H), 2.67-2.55 (m, 4H), 2.46-2.40 (m, 2H), 1.42-1.40 (m, 3H).

Example 84-Cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}pyridine-2-sulfonamideStep 1: 2-(Benzylthio)isonicotinonitrile

A 60% suspension of sodium hydride in mineral oil (8.36 g, 210.0 mmol)was suspended in tetrahydrofuran (100 mL). A solution of benzylmercaptan (21.5 g, 173 mmol) in tetrahydrofuran (50 mL) was then addeddropwise. A thick slurry formed during the addition.4-Cyano-2-chloropyridine (12.5 g, 90.2 mmol) was added and the resultingmixture was stirred for 3 hours at room temperature. After carefullyquenching with water, the mixture was partitioned between water anddiethyl ether. The ether layer was washed with saturated aqueous sodiumbicarbonate solution, dried over magnesium sulfate and concentratedunder reduced pressure. Heptane was added to the residue with solidsforming rapidly. The solids were collected by filtration, washed withheptane, and dried to give (33.02 g, 84%) of the title compound as anoff-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.61 (d, 1H), 7.25-7.46 (m,6H), 7.16-7.22 (m, 1H), 4.47 (s, 2H). LC/MS (exact mass) calculated forC₁₃H₁₀N₂S; 226.056. found (M+H⁺); 227.1.

Step 2: 4-cyanopyridine-2-sulfonyl chloride

To a mechanically-stirred mixture of 2-(benzylthio)isonicotinonitrile(8.92 g, 39.4 mmol) in dichloromethane (139 mL) and water (31 mL) wasadded dropwise sulfuryl chloride (22.5 mL, 278 mmol), keeping thetemperature of the mixture below 3° C. After addition was complete, themixture was stirred for 30 minutes with continued cooling in an icebath. A slurry of water (50 mL) and ice (20 g) was added. The aqueousphase was extracted twice with dichloromethane. The combined extractswere dried over magnesium sulfate and concentrated under reducedpressure to afford the crude title compound.

Step 3:4-Cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}pyridine-2-sulfonamide

A solution of 4-cyanopyridine-2-sulfonyl chloride (9.7 g, 47.9 mmol) inN,N-dimethylformamide (10 mL) was added to a solution ofcis-N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride (8.0 g, 36.8 mmol) and 4-dimethylaminopyridine (150 mg,0.03 mmol) in N,N-dimethylformamide (90 mL) at room temperature.Diisopropylethylamine (13 mL, 77 mmol) was added and the resultingmixture was stirred at room temperature for 2 hours. The mixture wasdiluted with ethyl acetate (200 mL) and aqueous saturated sodiumbicarbonate solution was added. Water was added to dissolve theprecipitated solids. The aqueous phase was extracted three times withethyl acetate. The combined organic extracts were washed four times withbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. A 1:1 mixture of ethyl acetate and hexanes was addedto the residue. The solids were collected by filtration and thendissolved in dichloromethane and a minimum amount of methanol. Theresulting solution was passed through a silica gel plug eluting with a5% solution of methanol in dichloromethane. The solvents were evaporatedto afford a solid to which was added a solution of 10% methanol indichloromethane. The mixture was briefly stirred and then let standovernight. The solids were filtered, washed with dichloromethane anddried to afford the title compound (5.58 g, 39%) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆): δ 11.62 (br. s., 1H), 9.02 (d, 1H), 8.52 (d,1H), 8.38 (s, 1H), 8.17 (dd, 1H), 8.07 (s, 1H), 7.10-7.15 (m, 1H), 6.59(dd, 3.41 Hz, 1H), 4.80-4.91 (m, 1H), 3.58-3.71 (m, 1H), 3.19 (s, 3H),2.25-2.36 (m, 2H), 2.10 (m, 2H). LC/MS (exact mass) calculated forC₁₇H₁₇N₇O₂S; 383.116. found (M+H⁺); 384.1.

Example 93-(1-Hydroxy-1-methylethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamideStep 1: Methyl3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}amino)-sulfonyl]benzoate

To a suspension ofcis-N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride (1.8 g, 8.29 mmol) in N,N-dimethylformamide (100 mL) wasadded portionwise triethylamine (6.7 mL, 49 mmol) at 0° C. Methyl3-(chlorosulfonyl)benzoate (2.3 g, 9.9 mmol) was added at 0° C. Theresulting mixture was stirred at room temperature for 3 hours. Thesolvent was removed under vacuum. The residue was chromatographed onsilica gel eluting with a gradient of methanol in dichloromethane (3% to10%) to afford the title compound (1.6 g, 47%) as a yellow solid.

Step 2:3-(Hydroxymethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamide

To a solution of methyl3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}amino)sulfonyl]benzoate(800 mg, 1.92 mmol) in tetrahydrofuran (120 mL) was added lithiumaluminum hydride (0.25 g, 6.7 mmol) at 0° C. The reaction was warmed to25° C. and stirred for 3 hours. The reaction was quenched with water (2mL) and stirred for 15 minutes. The reaction mixture was filtered. Thefilter cake was stirred in tetrahydrofuran (50 mL) and filtered again.The combined filtrate was concentrated to dryness to afford the titlecompound (430 mg, 58%) as a yellow solid.

Step 3:3-Formyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}benzenesulfonamide

To a solution of3-(hydroxymethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamide(400 mg, 1.03 mmol) in chloroform (50 mL) and methanol (5 mL) was addedmanganese dioxide (0.89 g, 10.0 mmol). The reaction mixture was stirredat 25° C. overnight. The reaction mixture was filtered and the filtercake was washed with chloroform (3×25 mL). The combined filtrates wereconcentrated. The residue was chromatographed on silica gel eluting witha gradient of methanol in dichloromethane (2% to 8%) to afford the titlecompound (240 mg, 60%) as an oil.

Step 4:3-(1-Hydroxyethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamide

To a solution of3-formyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamide(260 mg, 0.68 mmol) in tetrahydrofuran (20 mL) was added methylmagnesiumbromide (1.8 mL, 5.4 mmol) at 0° C. under nitrogen. The reaction wasstirred at 25° C. overnight and was then quenched with aqueous ammoniumchloride (10 mL). The reaction mixture was extracted with ethyl acetate(3 x25 mL). The combined organic layers were dried over sodium sulfateand concentrated. The residue was purified by preparative highperformance liquid chromatography to afford the title compound (60 mg,22%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.6 (s, 1H), 8.08(s, 1H), 8.03 (d, 1H), 7.86 (s, 1H), 7.70 (m, 1H), 7.55 (m, 2H), 7.15(m, 1H), 6.61 (m, 1H), 5.44 (m, 1H), 4.85 (m, 1H), 3.56 (m, 1H), 3.18(s, 3H), 2.18 (m, 2H), 2.04 (m, 2H), 1.32 (d, 3H). LC/MS (exact mass)calculated for C₁₉H₂₃N₅O₃S; 401.152. found (M+H⁺); 402.2.

Step 53-Acetyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclobutyl}benzenesulfonamide

To a solution of3-(1-hydroxyethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamide(60 mg, 0.15 mmol) in chloroform (30 mL) and methanol (5 mL) was addedmanganese dioxide (190 mg, 2.2 mmol). The reaction mixture was stirredat 45° C. overnight. Then the reaction mixture was filtered and thefilter cake was washed with chloroform (3×25 mL). The combined filtrateswere concentrated. The residue was purified by preparative highperformance liquid chromatography to afford the title compound (15 mg,25%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.58 (s, 1H), 8.31(s, 1H), 8.21 (m, 2H), 8.16 (m, 2H), 7.76 (m, 1H), 7.09 (d, 1H), 6.56(s, 1H), 4.82 (m, 1H), 3.54 (m, 1H), 3.14 (s, 3H), 2.81 (m, 3H), 2.26(m, 2H), 1.98 (m, 2H). LC/MS (exact mass) calculated for C₁₉H₂₁N₅O₃S;399.136. found (M+H⁺); 400.1.

Step 6:3-(1-Hydroxy-1-methylethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamide

To a solution of3-acetyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}benzenesulfonamide(240 mg, 0.58 mmol) in tetrahydrofuran (20 mL) was added methylmagnesiumbromide (2.4 mL, 7.2 mmol) at 0° C. under nitrogen. The reaction wasstirred at 25° C. for 2 hours and was quenched with aqueous ammoniumchloride solution (10 mL). The reaction mixture was extracted with ethylacetate (3×25 mL). The combined organic layers were dried over sodiumsulfate and concentrated. The residue was purified by preparative highperformance liquid chromatography to afford the title compound (101 mg,42%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.6 (s, 1H), 8.05(s, 1H), 7.97 (m, 2H), 7.67 (m, 2H), 7.52 (m, 1H), 7.12 (m, 1H), 6.57(m, 1H), 5.29 (s, 1H), 4.85 (m, 1H), 3.53 (m, 1H), 3.15 (s, 3H), 2.24(m, 2H), 1.98 (m, 2H), 1.44 (s, 6H). LC/MS (exact mass) calculated forC₂₀H₂₅N₅O₃S; 415.168, found (M+H⁺); 416.0.

Example 101-Cyclopropyl-N-{trans-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methanesulfonamide

This compound was synthesized starting from benzyl[trans-3-(methylamino)-cyclobutyl]carbamate (Example 1, Step 1),following procedures similar to those described for Example 1, Steps 2and 3 to obtaintrans-N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride. To the resulting hydrochloride (60 mg, 0.28 mmol) in THF(10 mL) was added potassium carbonate (76 mg, 0.55 mmol), H₂O (5 mL) andcyclopropylmethanesulfonyl chloride (52 mg, 0.33 mmol). The mixturestirred for two hours, was diluted with dichloromethane, washed withbrine, dried over sodium sulfate, filtered, and concentrated. The crudeproduct was purified by preparative high performance liquidchromatography to afford the title compound as a white solid (7 mg; 8%).¹H NMR (400 MHz, methanol-d₄): δ 8.14 (s, 1H), 7.16 (d, 1H), 6.72 (d,1H), 5.44-5.40 (m, 1H), 4.07-4.06 (m, 1H), 3.41 (s, 3H), 3.01-2.99 (m,2H), 2.81-2.74 (m, 2H), 2.54-2.49 (m, 2H), 1.15-1.13 (m, 1H), 0.720-0.69(m, 2H), 0.42-0.41 (m, 2H). LC/MS (exact mass) calculated forC₁₅H₂₁N₅O₂S; 335.142. found (M+H⁺); 336.1.

Example 11N-{(1S,3R)-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclopentyl}propane-1-sulfonamide

This compound was prepared following Example 10 substituting(1S,3R)—N-benzyl-N′-methylcyclopentane-1,3-diamine for benzyl[trans-3-(methylamino)-cyclobutyl]carbamate,(1R,3S)—N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclopentane-1,3-diaminehydrochloride fortrans-N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride, and propane-1-sulfonyl chloride forcyclopropylmethanesulfonyl chloride to afford the title compound as anoff-white solid (11%). The crude compound was purified using preparativehigh performance liquid chromatography. ¹H NMR (400 MHz, methanol-d₄): δ8.08 (s, 1H), 7.08 (s, 1H), 6.65 (s, 1H), 5.27-5.23 (m, 1H), 3.81-3.76(m, 1H), 3.31 (s, 3H), 2.33-2.29 (m, 1H), 2.13-2.04 (m, 1H), 1.98-1.92(m, 2H), 1.82-1.75 (m, 4H), 1.06 (t, 3H), 0.42-0.41 (m, 2H). LC/MS(exact mass) calculated for C₁₅H₂₃N₅O₂S; 337.157. found (M+H⁺); 337.8.

(1S,3R)—N-benzyl-N′-methylcyclopentane-1,3-diamine was prepared asfollows:

Step 1: Benzyl [(1R,3S)-3-aminocyclopentyl]carbamate

Trifluoroacetic acid (15 mL, 190 mmol) was added to a solution of benzyltert-butyl (1R,3S)-cyclopentane-1,3-diylbiscarbamate (prepared asdescribed in WO2011/086053A1) (5.02 g, 15.0 mmol) in dichloromethane (75mL) at room temperature. The reaction was stirred for 2 hours and wasthen concentrated to afford the title compound as a light brown oil(6.70 g, crude)

Step 2: Benzyl [(1R,3S)-3-(benzylamino)cyclopentyl]carbamate

Sodium triacetoxyhydroborate (4.38 g, 20.0 mmol) was added to a solutionof benzyl [(1R,3S)-3-aminocyclopentyl]carbamate (5.23 g, 15.0 mmol) andbenzaldehyde (1.7 mL, 16.0 mmol) in dichloromethane (75 mL) at roomtemperature. The mixture was stirred for 21 hours and then aqueous 1 Msodium hydroxide solution (75 mL) was added to make the solution basic.The aqueous layer was extracted with dichloromethane (2×25 mL). Thecombined organic layers were washed with brine (50 mL), dried oversodium sulfate and concentrated. The crude material was chromatographedon silica gel eluting with a mixture of dichloromethane and methanol(100:0 to 88:12) to afford the title compound as a yellow oil (3.47 g,71%). ¹H NMR (400 MHz, CDCl₃): δ 7.35-7.31 (m, 5H), 7.30-7.26 (m, 5H),5.07 (s, 2H), 4.17-4.07 (m, 1H) 3.76-3.68 (m, 2H), 3.27-3.20 (m, 1H),2.02-1.51 (m, 6H).

Step 3: (1S,3R)—N-Benzyl-N′-methylcyclopentane-1,3-diamine

Lithium aluminum hydride (1.02 g, 26.9 mmol) was added in portions to asolution of benzyl [(1R,3S)-3-(benzylamino)cyclopentyl]carbamate (3.47g, 10.7 mmol) in tetrahydrofuran (70 mL) at room temperature. Thereaction was heated to reflux for 3.5 hours. The mixture was then cooledin an ice bath and sequentially quenched with water (1.0 mL), aqueous15% sodium hydroxide solution (1.0 mL) and water (3.0 mL). Thesuspension was diluted with ethyl acetate and filtered through Celite.The filtrate was concentrated and the residue was taken up in aqueous0.5 M hydrochloric acid solution. The mixture was washed with diethylether (2×20 mL) and the aqueous solution was made basic (pH˜11) withsodium hydroxide. The resulting mixture was extracted withdichloromethane (3×25 mL). The combined organic layers were dried oversodium sulfate and concentrated. The crude material was chromatographedon silica gel eluting with a mixture of dichloromethane and methanol(90:10) to afford the title compound as a yellow oil (204 mg, 9%). ¹HNMR (400 MHz, CDCl₃): δ 7.33-7.20 (m, 5H), 3.74 (s, 2H), 3.19-3.13 (m,1H), 3.08-3.02 (m, 1H) 2.39 (s, 3H), 2.09-2.03 (m, 1H), 1.87-1.81 (m,2H), 1.67-1.54 (m, 2H), 1.46-1.39 (m, 1H). LC/MS (exact mass) calculatedfor C₁₃H₂₀N₂; 204.163. found (M+H⁺); 205.1.

Example 121-(3,3-Difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methanesulfonamideStep 1: Benzyl[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]carbamate

4-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (15 g,48.7 mmol) and benzyl [cis-3-(methylamino)cyclobutyl]carbamate (17.2 g,63.5 mmol) were mixed with isopropyl alcohol (180 mL) anddiisopropylethylamine (28 mL, 161 mmol). The resulting slurry was heatedat 75° C. for 6 hours. The reaction was cooled to room temperature,filtered, washed with isopropyl alcohol (150 mL) and dried in an oven at50° C. to give the title compound (23.5 g, 95%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 8.38 (s, 1H), 8.03 (d, 2H), 7.45 (d, 1H),7.38-7.28 (m, 4H), 7.26 (s, 1H), 7.25 (d, 1H), 6.61 (d, 1H), 5.08 (s,2H), 4.96 (d, 1H), 4.77 (m, 1H), 3.88 (m, 1H), 3.23 (s, 3H), 2.71 (m,2H), 2.36 (s, 3H), 2.18 (m, 2H).

Step 2cis-N-Methyl-N-{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diaminedihydrobromide

Benzyl[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]carbamate(15.2 g, 30.1 mmol) was suspended in ethyl acetate (45 mL) and aceticacid (45 mL). To the slurry was slowly added a 4M solution of HBr inacetic acid (45 mL, 180 mmol), maintaining the temperature below 25° C.The resulting slurry was stirred at room temperature for 2 hours. Thesolids were collected by filtration, washed with ethyl acetate (450 mL),and dried at 40° C. to afford the title compound (16 g; 100%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.31 (s, 1H), 8.20 (s, 2H), 7.97 (d,2H), 7.72 (d, 1H), 7.44 (d, 2H), 7.08 (d, 1H), 4.93 (m, 1H), 3.54 (m,1H), 3.30 (s, 3H), 2.50 (m, 4H), 2.35 (s, 3H). LC/MS (exact mass)calculated for C₁₈H₂₁N₅O₂S; 371.142. found (M+H⁺); 372.1.

Step 3: ({[(3,3-Difluorocyclobutyl)methyl]thio}methyl)benzene

A mixture of (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate(see WO2010/032200A1) (4 g, 14.5 mmol), benzyl imidothiocarbamate (3.53g, 17.4 mmol), sodium hydroxide solution (1.45 g, 36.2 mmol, dissolvedin 16 mL water) and N,N-dimethylformamide (16 mL) was stirred at 60° C.for 16 hours. Water (40 mL) and ethyl acetate (150 mL) were added. Theorganic layer was washed with water (40 mL), separated, dried oversodium sulfate and concentrated. The residue was chromatographed onsilica gel eluting with a gradient of petroleum ether and ethyl acetate(100:0 to 95:5) to afford the title compound as colorless oil (3.2 g,81%). ¹H NMR (400 MHz, CDCl₃): δ 7.34-7.24 (m, 5H), 5.71 (s, 2H),2.71-2.61 (m, 2H), 2.57-2.55 (m, 2H), 2.30-2.14 (m, 3H).

Step 4: (3,3-Difluorocyclobutyl)methanesulfonyl chloride

This compound was prepared following the procedure of Example 8 Step 2,substituting S-[3-(cyanomethyl)-3-methylcyclobutyl]ethanethioate for2-(benzylthio)isonicotinonitrile to afford the title compound as acolorless oil (93%). ¹H NMR (400 MHz, CDCl₃): δ 3.88-3.86 (m, 2H),3.03-2.94 (m, 3H), 2.61-2.49 (m, 2H).

Step 5:1-(3,3-difluorocyclobutyl)-N-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanesulfonamide

A solution of (3,3-difluorocyclobutyl)methanesulfonyl chloride (2.5 g,12.19 mmol) in 10 mL dichloromethane was added dropwise to a solution ofcis-N-methyl-N-{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diaminedihydrobromide (3.25 g, 6.10 mmol) and triethylamine (3.08 g, 30.49mmol) in dichloromethane (150 mL) at 0° C. over 15 minutes. The reactionwas stirred at room temperature for 4 hours. Water (50 mL) was added andthe organic layer was separated. The aqueous layer was extracted withdichloromethane (2×150 mL), and the combined organic layers wereseparated dried over sodium sulfate. The crude compound was purified bychromatography on silica gel eluting with a gradient of dichloromethaneand methanol (100:0 to 90:10) to afford the title compound as a whitesolid (2.0 g, 61%). LC/MS (exact mass) calculated for C₂₃H₂₇F₂N₅O₄S₂;539.147. found (M+H⁺); 540.1.

Step 6:1-(3,3-Difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methanesulfonamide

A solution of1-(3,3-difluorocyclobutyl)-N-[cis-3-(methyl{7-[(4-methylphenyl)-sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanesulfonamide(2 g, 3.71 mmol) and lithium hydroxide monohydrate (780 mg, 18.6 mmol)in ethanol (40 mL) and water (20 mL) was stirred at 60° C. for 4 hours.The ethanol was evaporated and the remaining aqueous layer wasneutralized to pH 7 with hydrochloric acid and subsequently extractedwith dichloromethane (2×200 mL). The combined organic layers was driedover sodium sulfate, filtered, concentrated, and purified by preparativehigh performance liquid chromatography to afford the title compound (800mg, 56%) as a white solid. ¹H NMR (400 MHz, methanol-d₄): δ 8.15 (s,1H), 8.13 (s, 1H), 7.16-7.15 (m, 1H), 6.73-6.62 (m, 1H), 4.95-4.88 (m,1H), 3.73-3.71 (m, 1H), 3.38 (s, 3H), 3.28-3.26 (m, 2 H), 2.87-2.78 (m,4H), 2.63-2.61 (m, 1H), 2.56-2.48 (m, 2H), 2.35-2.28 (m, 2H). LC/MS(exact mass) calculated for C₁₆H₂₁F₂N₆O₂S; 385.138. found (M+H⁺); 386.1.

The following compounds, Examples 13-14, were prepared fromcis-N-methyl-N-{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diaminedihydrobromide (Example 12, Step 2) in a similar manner to thatdescribed in Example 12, Step 5, substituting the indicated sulfonylchloride for (3,3-difluorocyclobutyl)methanesulfonyl chloride and usingthe deprotection method illustrated in Example 12, Step 6.

Example 133,3-Difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}cyclobutanesulfonamide

This compound was prepared using 3,3-difluorocyclobutanesulfonylchloride using the procedure in PCT Publication No. WO2011/068881. Thecrude compound was purified by chromatography on silica gel eluting witha gradient of petroleum ether and ethyl acetate (80:20 to 10:90) toafford the title compound as an off-white solid (22% over 2 steps). ¹HNMR (400 MHz, methanol-d₄): δ 8.13 (s, 1H), 7.13 (d, 1H), 6.70 (d, 1H),4.86-4.81 (m, 1H), 3.78-3.72 (m, 2H), 3.35 (s, 3H), 3.01-2.93 (m, 4H),2.78-2.76 (m, 2H), 2.32-2.25 (m, 2H). LC/MS (exact mass) calculated forC₁₆H₁₉F₂N₅O₂S; 371.123. found (M+H⁺); 372.1.

Example 141-Cyclopropyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methanesulfonamide

This compound was prepared as a white solid usingcyclopropylmethanesulfonyl chloride (73% over 2 steps). ¹H NMR (400 MHz,DMSO-d₆): δ 11.64 (br. s., 1H), 8.11 (s, 1H), 7.53 (d, 1H), 7.12-7.19(m, 1H), 6.64 (m, 1H), 4.84-4.97 (m, 1H), 3.54-3.70 (m, 1H), 3.26 (s,3H), 2.93 (d, 2H), 2.55-2.66 (m, 2H), 2.29-2.22 (m, 2H), 0.96-1.09 (m,1H), 0.53-0.64 (m, 2H), 0.29-0.39 (m, 2H). LC/MS (exact mass) calculatedfor C₁₆H₁₉F₂N₅O₂S; 335.142. found (M+H⁺); 336.0.

Example 151-Cyclopropyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}azetidine-3-sulfonamideStep 1: tert-Butyl3-({[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]amino}sulfonyl)azetidine-1-carboxylate

cis-N-Methyl-N-{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diaminedihydrobromide (7.0 g, 18.8 mmol) was free-based by stirring in excessaqueous 1N sodium hydroxide solution for 3 minutes and then extractinginto dichloromethane. The organic layer was dried over sodium sulfateand concentrated. The remaining free base was taken up indichloromethane (200 mL), cooled to 0° C. and treated with andtriethylamine (13 mL, 94 mmol) and tert-butyl3-(chlorosulfonyl)azetidine-1-carboxylate. The reaction was allowed tostir at room temperature for 10 minutes. The crude mixture was washedwith water and brine, then dried over sodium sulfate and concentrated toafford the crude product as a white solid. The solid was crystallizedusing a mixture of dichloromethane and diethyl ether to afford the titlecompound as a white solid (9.61 g, 90%). ¹H NMR (400 MHz, methanol-d₄):δ 8.19 (s, 1H), 7.92-8.01 (m, 2H), 7.54 (d, 1H), 7.35 (d, 2H), 6.86 (d,1H), 4.76-4.65 (m, 1H), 4.18 (br. s., 2H), 3.99-4.10 (m, 3H), 3.66-3.78(m, 1H), 3.25 (s, 3H), 2.64-2.78 (m, 2H), 2.37 (s, 3H), 2.10-2.25 (m,2H), 1.41 (s, 9H). LC/MS (exact mass) calculated for C₂₆H₃₄N₆O₆S₂;590.198. found (M+H⁺); 591.45.

Step 2:N-[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]azetidine-3-sulfonamide

Acetyl chloride (0.20 mL, 2.8 mmol) was added to a solution oftert-butyl3-({[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]amino}sulfonyl)azetidine-1-carboxylate(1.64 g, 2.78 mmol) in anhydrous dichloromethane (18 mL) and methanol (7mL) at 0° C. The reaction mixture was stirred at room temperature for 16hours. The white precipitate was filtered off and taken up in saturatedaqueous sodium bicarbonate solution (20 mL). The resulting solution wasextracted with dichloromethane (3×20 mL) and the combined organic layerswere dried over sodium sulfate and concentrated to afford the titlecompound (810 mg, 60%) as a white solid. LC/MS (exact mass) calculatedfor C₂₁H₂₆N₆O₄S₂, 490.146. found (M+H⁺); 491.0.

Step 3:1-Cyclopropyl-N-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]azetidine-3-sulfonamide

N-[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]azetidine-3-sulfonamide(810 mg, 1.65 mmol), methanol (10 mL), molecular sieves, and[(1-ethoxycyclopropyl)oxy](trimethyl)silane (0.53 mL, 2.64 mmol) werecombined in a sealable reaction vessel. The vessel was purged withnitrogen and acetic acid (1.28 mL, 8.26 mmol) was added. The vessel wassealed and then heated at 80° C. for 2 hours. After the mixture wascooled to room temperature, sodium cyanoborohydride (273 mg, 4.13 mmol)was added. The vessel was resealed and heated slowly to 40° C. for 1.5hours. The crude mixture was filtered over a bed of Celite, rinsing withmethanol. The filtrate was concentrated and the residue was taken up anaqueous saturated sodium bicarbonate solution. The resulting solutionwas extracted with dichloromethane (5×20 mL), and the combined organiclayers were dried over sodium sulfate and concentrated to afford thetitle compound (576 mg, 74%) as a white solid. ¹H NMR (400 MHz,methanol-d₄): δ 8.23 (s, 1H), 7.95-8.05 (m, 2H), 7.58 (d, 1H), 7.39 (d,2H), 6.90 (d, 1H), 4.69-4.83 (m, 1H), 3.94-4.09 (m, 1H), 3.65-3.75 (m,3H), 3.54-3.64 (m, 2H), 3.29 (s, 3H), 2.67-2.79 (m, 2H), 2.41 (s, 3H),2.15-2.29 (m, 2H), 2.02-2.15 (m, 1H), 0.43-0.51 (m, 2H), 0.29-0.39 (m,2H). LC/MS (exact mass) calculated for C₂₄H₃₀N₆O₄S₂; 530.177. found(M+H⁺); 531.0.

Step 4:1-Cyclopropyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}azetidine-3-sulfonamide

A solution of cesium carbonate (976 mg, 3.0 mmol) in water (5 mL) wasadded to a solution of1-cyclopropyl-N-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]azetidine-3-sulfonamide(530 mg, 1.0 mmol) in ethanol (10 mL). The reaction mixture was heatedto reflux for 16 hours. After the solvent was removed, remainingmaterial was taken up in water and extracted with a mixture ofdichloromethane and methanol (96:4; 3×10 mL). The combined organiclayers were dried over sodium sulfate and concentrated. The crude solidwas crystallized from methanol to afford the title compound (225 mg,59%) as a white solid. ¹H NMR (400 MHz, methanol-d₄): δ 8.10 (s, 1H),7.09 (d, 1H), 6.66 (d, 1H), 4.88-4.80 (m, 1H), 4.03-3.96 (m, 1H),3.73-3.65 (m, 3H), 3.61-3.57 (m, 2H), 3.32 (s, 3H), 2.77-2.68 (m, 2H),2.28-2.19 (m, 2H), 2.08-2.03 (m, 1H), 0.46-0.41 (m, 2H), 0.34-0.31 (m,2H). LC/MS (exact mass) calculated for C₁₇H₂₄N₆O₂S; 376.168. found(M+H⁺); 377.0.

Example 16N-(Cyclopropylmethyl)-N′-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}sulfamideStep 1:N-[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-2-oxo-1,3-oxazolidine-3-sulfonamide

To a solution of chlorosulfonyl isocyanate (1.76 mL, 20.6 mmol) indichloromethane (150 mL) was added dropwise a solution of 2-bromoethanol(1.43 mL, 20.6 mmol) in dichloromethane (80 mL) at 0° C. After 30minutes at 0° C., a solution ofcis-N-methyl-N-{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diaminedihydrobromide (11.0 g, 20.6 mmol) and triethylamine (10.42 g, 103.2mmol) in dry dichloromethane (80 mL) was added dropwise, and thereaction mixture was allowed to warm to room temperature overnight. Thereaction solution was dissolved in dichloromethane (1 L), washed withaqueous 1M hydrochloric acid solution (2×800 mL) and brine (500 mL). Thesolution was dried over sodium sulfate and concentrated to afford thetitle compound as white solid (8.5 g, 79%). ¹H NMR (400 MHz, CD₃OD): δ8.22 (s, 1H), 8.00 (d, 2H), 7.58 (d, 1H), 7.38 (d, 2H), 6.91 (d, 1H),4.88 (m, 1H), 4.45-4.41 (m, 2H), 4.06-4.02 (m, 2H), 3.75 (m, 1H), 3.29(s, 3H), 2.72-2.69 (m, 2H), 2.40 (s, 3H); 2.30-3.27 (m, 2H). LC/MS(exact mass) calculated for C₂₁H₂₄N₆O₆S₂; 520.120, found (M+H⁺); 521.4.

Step 2:N-(Cyclopropylmethyl)-N′-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]sulfamide

A solution ofN-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-2-oxo-1,3-oxazolidine-3-sulfonamide(150 mg, 0.29 mmol), cyclopropanemethylamine (51 mg, 0.72 mmol) andtriethylamine (116 mg, 1.15 mmol) in acetonitrile (3 mL) was stirred for15 minutes at 100° C. using microwave heating. The reaction mixture wasconcentrated to afford the crude title compound (146 mg, 100% crudeyield) as a yellow oil. LC/MS (exact mass) calculated for C₂₂H₂₈N₆O₄S₂;504.161. found (M+H⁺); 505.2.

Step 3:N-(Cyclopropylmethyl)-N′-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}sulfamide

A solution ofN-(cyclopropylmethyl)-N′-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]sulfamide(146 mg, 0.29 mmol), lithium hydroxide monohydrate (48 mg, 1.15 mmol) inethanol (5 mL) and water (2.5 mL) was stirred at 100° C. for 1 h. Thereaction mixture was concentrated under vacuum and the crude product waspurified by preparative high performance liquid chromatography to affordthe title compound (14 mg, 14%) as a white solid. ¹H NMR (400 MHz,methanol-d₄): δ 8.12 (s, 1H), 7.13 (d, 1H), 6.90 (d, 1H), 4.90-4.86 (m,1H), 3.63-3.59 (m, 1H), 3.37 (s, 3H), 2.85-2.83 (m, 2H), 2.78-2.71 (m,2H), 2.33-2.26 (m, 2H), 1.05-1.03 (m, 1H), 0.57-0.52 (m, 2H); 0.30-0.25(m, 2H). LC/MS (exact mass) calculated for C₁₅H₂₂N₆O₂S; 350.152. found(M+H⁺); 351.2.

The following compounds, Examples 17-18, were prepared fromN-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-2-oxo-1,3-oxazolidine-3-sulfonamide(Example 16, Step 1) in a similar manner to that described in Example16, Step 2, substituting the indicated amine forcyclopropanemethylamine, and using the deprotection method illustratedin Example 16, Step 3.

Example 17A and 17B (R)- and(S)-3-Cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}pyrrolidine-1-sulfonamide

These compounds were prepared using racemic pyrrolidine-3-carbonitrilehydrochloride. The crude racemic mixture was purified by highperformance liquid chromatography to afford a white solid (60 mg, 52%over 2 steps). The enantiomers were separated by supercritical fluidchromatography.

Enantiomer A (17A): 24 mg (21%): ¹H NMR (400 MHz, CD₃OD): δ 8.13 (s,1H), 7.13 (d, J=3.2 Hz, 1H), 6.69 (d, 1H, J=3.6 Hz, 1H), 4.87-4.84 (m,1H), 3.73-3.67 (m, 1H), 3.65-3.57 (m, 1H), 3.53-3.50 (m, 2H), 3.48-3.44(m, 2H), 3.405 (s, 3H), 2.77-2.75 (m, 2H), 2.42-2.20 (m, 4H). LC/MS(exact mass) calculated for C₁₆H₂₁N₇O₂S; 375.148, found (M+H⁺); 376.1.Chiral HPLC retention time=5.97 minutes.

Enantiomer B (17B): 25 mg (21%). ¹H NMR (400 MHz, CD₃OD): δ 8.13 (s,1H), 7.13 (d, J=3.2 Hz, 1H), 6.69 (d, 1H, J=3.6 Hz, 1H), 4.87-4.84 (m,1H), 3.73-3.67 (m, 1H), 3.65-3.57 (m, 1H), 3.53-3.50 (m, 2H), 3.48-3.44(m, 2H), 3.405 (s, 3H), 2.77-2.75 (m, 2H), 2.42-2.20 (m, 4H). LC/MS(exact mass) calculated for C₁₆H₂₁N₇O₂S; 375.148, found (M+H⁺); 376.1.Chiral HPLC retention time=5.16 minutes.

Example 182-Methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-sulfonamide

This compound was prepared using2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole hydrochloride. Thecrude compound was purified by high performance liquid chromatography toafford the title compound as an off-white solid (24% over 2 steps). ¹HNMR (400 MHz, methanol-d₄): δ 8.08 (s, 1H), 7.38 (s, 1H), 7.10 (d, 1H),6.66 (d, 1H), 4.87-4.86 (m, 1H), 4.42-4.41 (m, 4H), 3.87 (s, 3H),3.71-3.67 (m, 1H), 3.31 (s, 3H), 2.68-2.61 (m, 2H), 2.27-2.22 (m, 3H).LC/MS (exact mass) calculated for C₁₇H₂₂N₈O₂S; 402.159. found (M+H⁺);403.2 and (M+Na); 425.1.

Example 19N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-6-oxa-3-azabicyclo[3.1.1]heptane-3-sulfonamideStep 1:N-[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-6-oxa-3-azabicyclo[3.1.1]heptane-3-sulfonamide

A mixture ofN-[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-2-oxo-1,3-oxazolidine-3-sulfonamide(208 mg, 0.40 mmol), 6-oxa-3-azabicyclo[3.1.1]heptane (50 mg, 0.50mmol), triethylamine (220 μL, 1.58 mmol) in acetonitrile (15 mL), washeated in a 20 mL microwave vial in a microwave reactor for 1 hour at120° C. Excess solvent was evaporated and the resulting oil was taken upin dichloromethane. The solution was washed with aqueous ammoniumchloride and brine. The crude material was dried over sodium sulfate andconcentrated to give an oil. This was chromatographed on silica geleluting with a gradient methanol in dichloromethane (0:100 to 5:100) toafford the title compound as a foam (82 mg, 30%). ¹H NMR (CDCl₃): δ 8.38(s, 1H), 8.04 (d, 2H), 7.48 (d, 1H), 7.28 (d, 2H), 6.63 (d, 1H),4.78-4.69 (m, 1H), 4.62 (d, 1H), 4.47 (d, 1H), 3.69-3.61 (m, 1H), 3.58(d, 3H), 3.26-3.17 (m, 1H), 3.24 (s, 3H), 2.83-275 (m, 2H), 2.37 (s,3H), 2.18-2.11 (m, 2H), 2.04 (d, 1H), 1.18 (t, 1H). LC/MS (exact mass)calculated for C₂₃H₂₈N₆O₅S₂; 532.156. found (M+H⁺); 533.

Step 2:N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-6-oxa-3-azabicyclo[3.1.1]heptane-3-sulfonamide

N-[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-6-oxa-3-azabicyclo[3.1.1]heptane-3-sulfonamide(229 mg, 0.43 mmol) was added to a solution of in 1M tetrabutylammoniumfluoride in tetrahydrofuran (6.5 mL, 6.4 mmol). The reaction was stirredat room temperature for 10 hours. The mixture was concentrated and theremaining material was chromatographed on silica gel eluting with amixture of methanol in ethyl acetate (1:9). A yellow oil was isolatedthat was triturated with a mixture of ethyl acetate and heptane to givea yellow solid. The solid was partitioned between ethyl acetate andwater. The aqueous layer was extracted with ethyl acetate and thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated to afford an off-white solid. This wastriturated with diethyl ether and then isopropyl alcohol to afford thetitle compound as a white solid (14 mg, 9%). ¹H NMR (CD₃OD) δ 8.08 (s,1H), 7.09 (d, 1H), 6.66 (s, 1H), 4.90-4.81 (m, 1H), 4.62 (d, 2H),3.86-8.84 (m, 1H), 3.66 (t, 1H), 3.56-3.49 (m, 3H), 3.33 (s, 3H),3.19-3.13 (m, 1H), 2.75-2.70 (m, 2H), 2.32-2.24 (m, 2H), 2.05-2.03 (d,1H). LC/MS (exact mass) calculated for C₁₆H₂₂N₆O₃S; 378.147. found(M+H⁺); 379.5.

The following compounds, Examples 20-24, were prepared fromN-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-2-oxo-1,3-oxazolidine-3-sulfonamide(Example 16, Step 1) in a similar manner to that described in Example16, Step 2, substituting the indicated amine forcyclopropanemethylamine, and using the deprotection method illustratedin Example 19, Step 2.

Example 203-Cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-c]pyrimidin-4-yl)amino]-cyclobutyl}azetidine-1-sulfonamide

This compound was prepared using azetidine-3-carbonitrile. The crudecompound was purified by high performance liquid chromatography toafford the title compound as a white solid (23% over 2 steps). ¹H NMR(400 MHz, CD₃OD): δ 8.10 (s, 1H), 7.11 (d, 1H), 6.68 (d, 1H), 4.80 (m,1H), 4.02 (m, 2H), 3.90 (m, 2H), 3.58 (m, 2H), 3.32 (s, 3H), 2.72 (m,2H), 2.25 (m, 2H). LC/MS (exact mass) calculated for C₁₅H₁₉N₇O₂S;361.132. found (M+H⁺); 362.1.

Example 21N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-4-(1H-pyrazol-3-yl)piperidine-1-sulfonamide

This compound was prepared using 4-(1H-pyrazol-3-yl)piperidine. Thecrude compound was purified by chromatography on silica gel eluding witha mixture of dichloromethane and methanol (9:1). The isolated materialwas triturated with diethyl ether and then ethyl acetate to afford thetitle compound as a white solid (10% over 2 steps). ¹H NMR (300 MHz,CD₃OD): δ 8.09 (s, 1H), 7.48 (s, 1H), 7.12-7.05 (m, 1H), 6.71-6.60 (m,1H), 6.22-6.08 (m, 1H), 4.92-4.73 (m, 1H), 3.80-3.55 (m, 3H), 3.41 (s,3H), 2.90-2.65 (m, 5H), 2.38-2.19 (m, 2H), 2.09-1.90 (m, 2H) and1.83-1.65 (m, 2H). LC/MS (exact mass) calculated for C₁₉H₂₆N₈O₂S;430.190. found (M+H⁺); 431.1.

Example 22N-(2-Cyanoethyl)-N-methyl-N′-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}sulfamide

This compound was prepared using 3-methylaminopropionitrile. The crudecompound was purified by high performance liquid chromatography toafford the title compound (7% over 2 steps). LC/MS (exact mass)calculated for C₁₅H₂₁N₇O₂S; 363.148, found (M+H⁺); 364.0.

Example 23 and 27(1S,5S)-1-Cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-3-azabicyclo[3.1.1]hexane-3-sulfonamideand(1R,5R)-1-Cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-c]pyrimidin-4-yl)amino]cyclobutyl}-3-azabicyclo[3.1.0]hexane-3-sulfonamide

These compounds were prepared using racemic3-azabicyclo[3.1.0]hexane-1-carbonitrile. The crude racemic compound waspurified as a white solid (92 mg, 21% over 2 steps) by chromatography onsilica gel eluting with a gradient of dichloromethane and methanol (30:1to 5:1). The title enantiomers were separated by supercritical fluidchromatography.

Enantiomer 23: 41 mg (9%); SFC retention time=4.28 minutes; ¹H NMR (400MHz, methanol-d₄): δ 8.13 (s, 1H), 7.13 (d, 1H), 6.70 (d, 1H), 4.61 (s,1H), 3.57-3.72 (m, 2H), 3.43-3.51 (m, 3H), 3.36 (s, 3H), 2.70-2.77 (m,2H), 2.24-2.38 (m, 3H), 1.41-1.48 (m, 1H), 1.32 (t, 1H). LC/MS (exactmass) calculated for C₁₇H₂₁N₇O₂S; 387.148, found (M+H⁺); 388.1.

Enantiomer 27: 40 mg (9%); SFC retention time=4.84 minutes ¹H NMR (400MHz, methanol-d₄): δ 8.13 (s, 1H), 7.13 (d, 1H), 6.70 (d, 1H), 4.61 (s,1H), 3.57-3.72 (m, 2H), 3.43-3.51 (m, 3H), 3.36 (s, 3H), 2.70-2.77 (m,2H), 2.24-2.38 (m, 3H), 1.41-1.48 (m, 1H), 1.32 (t, 1H). LC/MS (exactmass) calculated for C₁₇H₂₁N₇O₂S; 387.148, found (M+H⁺); 388.1.

Racemic 3-azabicyclo[3.1.0]hexane-1-carbonitrile was prepared asfollows.

Step 1: Racemic tert-butylrac-1-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (6.5 g, 15.2mmol) was added to a solution of racemictert-butyl-1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(Synlett 2009, 921) (2.5 g, 11.7 mmol) in anhydrous dichloromethane (60mL). The reaction mixture stirred for 2 hours at room temperature. Themixture was diluted with dichloromethane (60 mL), washed with asaturated aqueous solution of sodium sulfite, saturated sodiumbicarbonate (30 mL) and brine (50 mL). The organic layer was dried oversodium sulfate and concentrated to give afford the title compound as acolorless oil (1.7 g, 68%). ¹H NMR (400 MHz, CDCl₃): δ 9.01 (d, 1H),3.83 (d, 1H), 3.68 (t, 1H), 3.59 (dd, 1H), 3.50-3.36 (m, 1H), 2.25-2.09(m, 1H), 1.63 (t, 1H), 1.43 (s, 9H), 1.19-1.06 (m, 1H).

Step 2: Racemictert-butyl-1-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

Potassium carbonate (3.89 g, 28.2 mmol) and hydroxylamine hydrochloride(671 mg, 9.7 mmol) were added to a solution of tert-butyl racemic1-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.7 g, 8.05 mmol) inanhydrous dichloromethane (40 mL) at room temperature and then stirredfor 16 hours. The mixture was diluted with ethyl acetate (80 mL), andwashed with water (30 mL) and brine (30 mL). The organic layer was driedover sodium sulfate and concentrated. The residue was chromatographed onsilica gel eluting with a gradient of petroleum ether and ethyl acetate(0:100 to 83:17) to afford the title compound as a yellow oil (1.6 g,88%). ¹H NMR (400 MHz, CDCl₃): δ 7.18 (s, 1H), 3.74-3.55 (m, 3H),3.44-3.40 (m, 1H), 1.74-1.72 (m, 1H), 1.44 (s, 9H), 1.10 (t, 1H),0.86-0.83 (m, 1H).

Step 3: Racemictert-butyl-1-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of racemictert-butyl-1-[(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(925 mg, 4.09 mmol) in anhydrous tetrahydrofuran (100 mL) was addedmethyl N-(triethylammonium sulfonyl)carbamate (2.92 g, 12.3 mmol). Thereaction mixture was heated to reflux for 3 hours. After evaporation ofthe solvent, the residue was chromatographed on silica gel eluting witha mixture of petroleum ether and ethyl acetate (5:1) to afford the titlecompound as a colorless oil (570 mg, 67%). ¹H NMR (400 MHz, CDCl₃): δ3.84 (dd, 1H), 3.64 (dd, 1H), 3.50 (d, 1H), 3.46 (dd, 1H), 2.21-2.12 (m,1H), 1.44 (s, 9H), 0.96 (t, 1H).

Step 4: Racemic 3-azabicyclo[3.1.0]hexane-1-carbonitrile

A solution of racemictert-butyl-1-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate intrifluoroacetic acid (1 mL) and dichloromethane (10 mL) was stirred atroom temperature for 1 hour. The solvent was removed to afford the titlecompound (205 mg, 100%) as a brown oil.

Example 24 Racemic3-cyano-N-{trans-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}pyrrolidine-1-sulfonamide

This compound was synthesized following the procedure of Example 10,substituting 3-cyanopyrrolidine-1-sulfonyl chloride forcyclopropylmethanesulfonyl chloride. The crude product was purifiedusing preparative high performance liquid chromatography to afford thetitle compound as an off-white solid (5%). ¹H NMR (400 MHz, CD₃OD): δ8.13 (s, 1H), 7.14 (d, 1H), 6.67 (d, 1H), 5.45-5.41 (m, 1H), 4.00-3.64(m, 1H), 3.62-3.52 (m, 1H), 3.51-3.47 (m, 2H), 3.45-3.39 (m, 2H), 3.369(s, 3H), 2.78-2.70 (m, 2H), 2.53-2.47 (m, 2H); 2.39-2.36 (m, 1H);2.27-2.24 (m, 1H). LC/MS (exact mass) calculated for C₁₆H₂₁N₇O₂S;375.148. found (M+H⁺); 375.9.

Racemic 3-cyanopyrrolidine-1-sulfonyl chloride

A solution of racemic pyrrolidine-3-carbonitrile (53 mg, 0.4 mmol) andtriethylamine (101 g, 1 mmol) in dry dichloromethane (1.0 mL) was addeddropwise to a stirred solution of sulfuryl chloride (64.8 mg, 0.48 mmol)in dichloromethane (3.0 mL) was added at −78° C. The reaction wasstirred at −78° C. for 30 minutes, and then allowed to warm to roomtemperature over 1 hour. The reaction solution was washed with aqueous1M hydrochloric acid (5 mL) and brine (5 mL), dried over sodium sulfateand concentrated to afford the title compound as colorless oil (68 mg,crude).

Example 25N-(cis-3-{[(4,4-Difluoropiperidin-1-yl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineStep 1: cis/trans-Ethyl3-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylate

To a solution of a mixture of cis- and trans-ethyl 3-aminocyclobutanecarboxylate hydrochloride (cis/trans=10:1) (WO2009/60278)(10 g, 55.7 mmol) and triethylamine (19.4 mL, 139.1 mmol.) indichloromethane (370 mL) at 0° C. was added dropwise di-tert-butyldicarbonate (15.8 g, 72.3 mmol). After addition was complete, themixture was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the resulting residue waschromatographed on silica gel eluting with a gradient of petroleum etherand ethyl acetate (10:1 to 3:1) to afford the title mixture as a whitesolid (19 g, 92%). ¹H NMR (400 MHz, CDCl₃): δ 4.77 (s, 1H), 4.13 (q,3H), 2.68-2.82 (m, 1H), 2.60 (d, 2H), 1.99-2.17 (m, 2H), 1.43 (s, 9H),1.25 (t, 3H).

Step 2: cis/trans-[3-(Methylamino)cyclobutyl]methanol

Lithium aluminum hydride (9.14 g, 240.4 mmol) was suspended in drytetrahydrofuran (350 mL). The mixture was cooled to 0° C. and a solutionof cis/trans ethyl 3-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylate(cis/trans=10:1) (11.7 g, 48.1 mmol) in dry tetrahydrofuran (170 mL) wasadded drop wise. After addition was complete, the resulting mixture washeated to reflux overnight. After it was cooled to room temperature, thereaction was diluted with tetrahydrofuran (1.5 L) and then cooled to0˜5° C. Small portions of Na₂SO₄.10H₂O were added until gas evolutionhad ceased. The mixture was filtered to remove the solids, which werewashed with more tetrahydrofuran (500 mL). The filtrate was concentratedto dryness affording the title mixture (cis/trans=10:1) as an oil (10g, >100%). ¹H NMR (400 MHz, CDCl₃): δ 3.58 (d, J=3.8 Hz, 2H), 3.06-3.17(m, 1H), 2.34-2.43 (m, 3H), 2.32 (s, 3H), 1.48-1.57 (m, 2H).

Step 3:cis/trans-[3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanol

Potassium iodide (173 mg) and triethylamine (13 mL, 93.8 mmol) wereadded to a solution of cis/trans-[3-(methylamino)cyclobutyl]methanol(6.0 g, 52.1 mmol) in acetone (250 mL).4-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (14.4g, 46.9 mmol) was then added and the resulting mixture was heated toreflux overnight. After evaporation of the solvent under reducedpressure, the residue was diluted with dichloromethane (500 mL). Thesolution was washed sequentially with water (300 mL), 2% aqueous citricacid (300 mL) and brine (300 mL), and then dried over sodium sulfate.After filtration, the solution was filtered and concentrated to affordthe title mixture as a light solid (15.3 g, 85%). A portion (5.0 g) ofthecis/trans-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanolmixture was separated by supercritical fluid chromatography using aChiralpak-AD column: cis isomer, 4.6 g: ¹H NMR (400 MHz, methanol-d₄): δ8.20 (s, 1H), 7.98 (d, 2H), 7.53 (d, 1H), 7.34 (d, 2H), 6.83 (d, 2H),4.99-4.95 (m, 1H), 3.56 (d, J=5.6 Hz, 1H), 3.24 (s, 3H), 2.36 (s, 3H),2.34-2.28 (m, 2H), 2.24-2.19 (m, 1H), 2.11-2.03 (m, 2H). LC/MS (exactmass) calculated for C₁₉H₂₂N₄O₃S: 386.14. found (M+H⁺): 387.3 transisomer, 0.4 g: ¹H NMR (400 MHz, methanol-d₄): δ 8.20 (s, 1H), 7.98 (d,2H), 7.55 (d, 1H), 7.35 (d, 2H), 6.84 (d, 2H), 5.26-5.22 (m, 1H), 3.69(d, 1H), 3.30 (s, 3H), 2.46-2.41 (m, 3H), 2.39 (s, 3H), 2.19-2.14 (m,2H). LC/MS (exact mass) calculated for C₁₉H₂₂N₄O₃S: 386.14. found(M+H⁺): 387.3.

Step 4:cis-[3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl4-methylbenzenesulfonate

To a solution ofcis-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanol(20 g, 51.8 mmol) and N,N-dimethylaminopyridine (12.6 g, 103.6 mmol) indichloromethane (500 mL) at 0° C. was added p-toluenesulfonyl chloride(14.8 g, 77.7 mmol). The reaction mixture was stirred at roomtemperature for 16 hours and then washed with water (500 mL). Thecombined aqueous washes were extracted with dichloromethane (2×800 mL).The combined organic layers were dried, filtered and concentrated undervacuum. The residue was chromatographed on silica gel eluting with agradient of dichloromethane and methanol (100:0 to 95:5) to afford thetitle compound (23 g, 82%) as a white solid. LC/MS (exact mass)calculated for C₂₆H₂₈N₄O₅S₂: 540.150. found (M+H⁺): 541.3.

Step 5:S-{[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}ethanethioate

To a solution of potassium thioacetate (678 mg, 5.93 mmol) inN,N-dimethylformamide (5 mL) was added a solution of[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl4-methylbenzenesulfonate (2.0 g, 3.70 mmol) in N,N-dimethylformamide (6mL) dropwise over 5 minutes at room temperature. The mixture was thenheated to at 50-55° C. overnight. The mixture was cooled to roomtemperature and quenched by pouring into aqueous saturated sodiumbicarbonate solution (60 mL). The mixture was extracted with ethylacetate (3×30 mL) and the combined organic layers were washed with water(3×30 mL), brine (30 mL). After drying over Na₂SO₄ the solution wasconcentrated. The residue was chromatographed on silica gel eluting witha gradient of dichloromethane and methanol (100:0 to 80:20) to affordthe title compound (1.2 g, 73%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃): δ 8.39 (s, 1H), 8.04 (d, 2H), 7.45 (d, 1H), 7.27 (d, 2H), 6.63(d, 1H), 4.98-4.88 (m, 1H) 3.22 (s, 3H) 3.02-3.00 (m, 2H) 2.45-2.44 (m,2H), 2.47 (m, 3H) 2.22 (m, 3H) 2.21-2.24 (m, 1H) 1.92-1.87 (m, 2H).LC/MS (exact mass) calculated for C₂₁H₂₄N₄O₃S₂: 444.129. found (M+H⁺):445.1.

Step 6:[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanesulfonicacid

To a solution ofS-{[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}ethanethioate(580 mg, 1.31 mmol), in formic acid (10 mL) at room temperature wasadded 30% aqueous hydrogen peroxide solution (0.7 mL, 6.92 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction was poured into an aqueous 33% aqueous sodium bisulfatesolution (1.12 mL) and then stirred for 10 minutes. Aqueous 33% sodiumhydroxide solution (1.8 mL) was then added to adjust the pH to 5. Theresulting mixture was stirred at room temperature for 1 hour. The solidwas collected solid by filtration, washed with water (10 mL) and vacuumdried at about 60° C. to afford the title compound (634 mg, crude) as awhite solid. LC/MS (exact mass) calculated for C₁₉H₂₂N₄O₅S₂; 450.103.found (M+H⁺); 451.3.

Step 7:cis-[3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanesulfonylchloride

Thionyl chloride (0.3 ml, 3.33 mmol) was added dropwise over 5 minutesto a solution ofcis-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanesulfonicacid (150 mg, 0.33 mmol) in dichloromethane (20 mL) at 0° C. Two dropsof N,N-dimethylformamide were added to the solution, which was thenheated at 75° C. for 2 hours. The mixture was cooled and the solvent wasevaporated. The residue was washed with anhydrous dichloromethane (3×10mL) to afford the crude title compound (170 mg) as a yellow solid. LC/MS(exact mass) calculated for C₁₉H₂₁CIN₄O₄S₂; 468.069. found (M+H⁺);469.2.

Step 8:N-(cis-3-{[(4,4-Difluoropiperidin-1-yl)sulfonyl]methyl}cyclobutyl)-N-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-c]pyrimidin-4-amine

To a mixture of 4,4-difluoropiperidine (77 mg, 0.64 mmol) andtriethylamine (97 mg, 0.96 mmol) in tetrahydrofuran (20 mL) at 0° C. wasadded dropwise a solution ofcis-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanesulfonylchloride (150 mg, 0.320 mmol) in tetrahydrofuran (10 mL). The mixturewas allowed to warm to room temperature overnight. The solvent wasevaporated and the residue was taken up in ethyl acetate (80 mL). Thesolution was washed with brine (30 mL), dried over sodium sulfate andconcentrated to afford the crude title compound (134 mg) as a whitesolid. LC/MS (exact mass) calculated for C₂₄H₂₉F₂N₅O₄S₂; 553.651. found(M+H⁺); 554.3.

Step 9:N-(cis-3-{[(4,4-difluoropiperidin-1-yl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

N-(cis-3-{[(4,4-Difluoropiperidin-1-yl)sulfonyl]methyl}cyclobutyl)-N-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(134 mg, 0.24 mmol) and lithium hydroxide monohydrate (51 mg, 1.21 mmol)were combined in a mixture of ethanol (14 mL) and water (7 mL) and thenheated at 50° C. overnight. The reaction was concentrated under vacuumand diluted with ethyl acetate (100 mL). The resulting solution waswashed with brine (30 mL), dried over sodium sulfate and concentrated.The residue was chromatographed using preparative thin layerchromatography eluting with a mixture of ethyl acetate and methanol(20:1) to afford the title compound (31 mg, 32.3%) as a white solid. ¹HNMR (400 MHz, methanol-d₄): δ 8.13 (s, 1H), 7.13 (d, J=3.6, 1H), 6.70(d, J=3.6, 1H), 5.12 (m, 1H), 3.49-3.47 (m, 4H), 3.46 (m, 3H), 3.33 (m,2H), 2.62-2.54 (m, 3H), 2.25-2.20 (m, 1H), 2.11-2.05 (m, 2H). LC/MS(exact mass) calculated for C₁₇H₂₃F₂N₅O₂S; 399.154. found (M+H⁺); 400.3.

Examples 26 to 29

The following compounds were made starting fromcis-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methanesulfonylchloride (Example 25, Step 7), according to the procedures of Example25, Step 8 (sulfonylation) and step 9 (deprotection), substituting theappropriate amine for 4,4-difluoropiperidine in Step 8.

Example 261-[({cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methyl)sulfonyl]-4-(trifluoromethyl)piperidin-4-ol

The title compound (31 mg) was prepared using4-(trifluoromethyl)piperidin-4-ol in the sulfonylation step and wasdeprotected using the method from Example 25, Step 9. The compound waspurified using preparative thin layer chromatography eluting witheluting with a mixture of ethyl acetate and methanol (20:1). ¹H NMR (400MHz, methanol-d₄): δ 8.13 (s, 1H), 7.13 (d, J=3.6, 1H), 6.70 (d, J=3.6,1H), 5.10-5.08 (m, 1H), 3.74-3.71 (m, 2H), 3.36 (m, 3H), 3.32-3.27 (m,2H), 3.19-3.13 (m, 2H), 2.62-2.54 (m, 3H), 2.25-2.21 (m, 2H), 1.86-1.84(m, 4H). LC/MS (exact mass) calculated for C₁₈H₂₄F₃N₅O₃S; 447.155. found(M+H⁺); 448.3.

Example 28 and 29 (3R) and(3S)-1-[({cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyrrolidine-3-carbonitrile

The title compounds (330 mg total) were prepared usingpyrrolidine-3-carbonitrile enriched as an 80:20 scalemic mixture of(3R)-pyrrolidine-3-carbonitrile and (3S)-pyrrolidine-3-carbonitrileenantiomers in the sulfonylation step and was de-protected using themethod from Example 19, Step 2. The compound was purified bychromatography on silica gel eluting with gradient of petroleum etherand ethyl acetate (10:1 to 1:10). LC/MS m/z=375.2 (M+1). The enantiomerswere separated by preparative supercritical fluid chromatography:

3R-enantiomer(28): 178 mg. ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 7.06(d, 1H), 6.58 (d, 1H), 5.19-5.10 (m, 1H), 3.77-3.75 (m, 1H), 3.61-3.54(m, 3H), 3.33 (s, 3H), 3.21-3.19 (m, 3H), 2.69-2.66 (m, 3H), 2.36-2.31(m, 2H), 2.14-2.11 (m, 2H). LC/MS (exact mass) calculated forC₁₇H₂₂N₆O₂S; 374.15. found (M+H⁺); 375.2. Chiral HPLC retentiontime=2.65 minutes.

3S-enantiomer(29): 31 mg. ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 7.06(d, 1H), 6.58 (d, 1H), 5.19-5.10 (m, 1H), 3.77-3.75 (m, 1H), 3.61-3.54(m, 3H), 3.33 (s, 3H), 3.21-3.19 (m, 3H), 2.69-2.66 (m, 3H), 2.36-2.31(m, 2H), 2.14-2.11 (m, 2H). LC/MS (exact mass) calculated forC₁₇H₂₂N₆O₂S; 374.15. found (M+H⁺); 375.2 Chiral HPLC retention time=2.53minutes.

Example 30N-{cis-3-[(Butylsulfonyl)methyl]cyclobutyl}-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineStep 1:N-{cis-3-[(Butylthio)methyl]cyclobutyl}-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A solution ofcis-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl4-methylbenzenesulfonate from Example 25, Step 4 (23 g, 42.6 mmol) wasstirred in N-methylpyrrolidine (100 mL). Then1,8-diazabicycloundec-7-ene (12.8 g, 85.2 mmol) and 1-butanethiol (7.8g, 85.2 mmol) was added to the reaction mixture. The reaction wasstirred at room temperature for 16 hours. Water (200 mL) and ethylacetate (500 mL) were added. The aqueous layer was extracted with ethylacetate (2×500 mL) and the combined organic layers were dried andconcentrated. The residue was chromatographed on silica gel eluting witha gradient of dichloromethane and methanol (100:0 to 90:10) to affordthe title compound (11.8 g, 91%). LC/MS (exact mass) calculated forC₁₆H₂₄N₄S; 304.172. found (M+H⁺); 305.3.

Step 2:N-{cis-3-[(Butylsulfonyl)methyl]cyclobutyl}-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

N-{cis-3-[(Butylthio)methyl]cyclobutyl}-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(12 g, 39.5 mmol) was dissolved in a mixture of tetrahydrofuran (200mL), ethanol (200 mL) and water (200 mL). Potassium peroxomonosulfate(48.6 g, 79.0 mmol) was added and the reaction was stirred at roomtemperature for 1 hour. The mixture was then filtered; the solids werewashed with a mixture of tetrahydrofuran (40 mL), ethanol (40 mL) andwater (20 mL). The filtrate was treated with aqueous 10% sodiumbisulfite solution (200 mL) and stirred at room temperature for 20minutes. A saturated solution of aqueous sodium bicarbonate was added toadjust the pH to −7. The mixture was extracted with dichloromethane(3×800 mL) and the combined organic layers were dried and concentratedunder vacuum. The crude residue was chromatographed on silica geleluting with a gradient of dichloromethane and methanol (100:0 to 95:5)to obtain the title compound (11.4 g, 86%). ¹H NMR (400 MHz,methanol-d₄): δ 8.13 (s, 1H), 7.13-7.12 (m, 1H), 6.70-6.69 (m, 1H),5.13-5.10 (m, 1H), 3.42 (s, 3H), 3.33 (m, 2H), 3.11-3.07 (m, 2H),2.65-2.63 (m, 3H), 2.29-2.25 (m, 2H), 1.86-1.78 (m, 2H), 1.55-1.50 (m,2H), 1.03-0.99 (m, 3H). LC/MS (exact mass) calculated for C₁₆H₂₄N₄O₂S;336.162. found (M+H⁺); 337.3.

Example 31N-Methyl-N-(trans-3-((propylsulfonyl)methyl)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The title compounds were made as a mixture of cis and trans isomers (50mg) starting from cis andtrans-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl4-methylbenzene sulfonate (cis/trans=10:1) (Example 25, Step 4),according to procedures similar to those of Example 30, Steps 1 and 2,using propane-1-thiol instead of butane-1-thiol in Step 2. The mixtureof cis and trans isomers was purified by reverse phase high performanceliquid chromatography eluting with gradient of water and acetonitrile(95:5 to 5:95). LC/MS (exact mass) calculated for C₁₅H₂₂N₄O₂S; 322.15.found (M+H⁺); 323.2.

The cis and trans isomers were then separated by preparativesupercritical fluid chromatography.

trans isomer (31), 12 mg: ¹H NMR (400 MHz, methanol-d₄): δ 8.12 (s, 1H),7.13-7.12 (m, 1H), 6.69-6.66 (m, 1H), 5.45-5.41 (m, 1H), 3.46-3.44 (m,2H), 3.36 (s, 3H), 3.11-3.09 (m, 2H), 2.88-2.86 (m, 1H), 2.75-2.67 (m,2H), 2.40-2.38 (m, 2H), 1.91-1.86 (m, 2H), 1.12-1.10 (m, 3H). LC/MS(exact mass) calculated for C₁₅H₂₂N₄O₂S; 322.15. found (M+H⁺); 323.2.

cis isomer, 36 mg: ¹H NMR (400 MHz, methanol-d₄): δ 8.12 (s, 1H),7.13-7.12 (m, 1H), 6.70-6.69 (m, 1H), 5.10-5.20 (m, 1H), 3.36 (s, 3H),3.33-3.32 (m, 2H), 3.08-3.04 (m, 2H), 2.64-2.61 (m, 3H), 2.24-2.22 (m,2H), 1.90-1.84 (m, 2H), 1.13-1.09 (m, 3H). LC/MS (exact mass) calculatedfor C₁₅H₂₂N₄O₂S; 322.15. found (M+H⁺); 323.2.

Example 32N-(cis-3-{[(2-Cyclopropylethyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineStep 1:N-(cis-3-{[(2-Cyclopropylethyl)sulfanyl]methyl}cyclobutyl)-N-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-c]pyrimidin-4-amine

Nitrogen was bubbled through a mixture ofS-{[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}ethanethioateExample 25, Step 5 (190 mg, 0.43 mmol) and potassium carbonate (129 mg,0.94 mmol) in methanol (10 mL) at 0° C. for 2 minutes.2-Cyclopropylethyl 4-methylbenzenesulfonate (159 mg, 1.53 mmol) was thenadded and the solution was stirred for 6 hours at room temperature.Dichloromethane (30 mL) and water (20 mL) were added and the aqueouslayer was extracted with dichloromethane (2×20 mL). The combined organiclayers were washed with brine, dried over sodium sulfate andconcentrated. The crude product was purified by preparative thin layerchromatography using ethyl acetate-petroleum ether (1:2) to give thetitle compound as a white solid (62 mg, 31%). LC/MS (exact mass)calculated for C₂₄H₃₀N₄O₂S₂; 470.18. found (M+H⁺); 471.1.

Step 2:N-(cis-3-{[(2-Cyclopropylethyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The mixture ofN-(cis-3-{[(2-cyclopropylethyl)sulfanyl]-methyl}cyclobutyl)-N-methyl-7-[(4-methylphenyl)-sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(24 mg, 0.051 mmol) and potassium peroxomonosulfate (49 mg, 0.079 mmol)in tetrahydrofuran (1.2 mL), water (0.6 mL) and ethanol (1.2 mL) wasstirred at room temperature for 20 minutes. Aqueous sodium bisulfite wasadded, followed by dichloromethane (20 mL). The aqueous layer wasextracted with dichloromethane (2×20 mL) and the combined organic layerswere extracted with brine, dried over sodium sulfate and concentrated.The crude material was used directly in next step. LC/MS (exact mass)calculated for C₂₄H₃₀N₄O₄S₂; 502.17. found (M+H⁺); 503.3.

Step 3:N-(cis-3-{[(2-Cyclopropylethyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The mixture ofN-(cis-3-{[(2-cyclopropylethyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(49 mg, 0.097 mmol) and lithium hydroxide (30 mg, 1.3 mmol) in water (5mL) and ethanol (10 mL) was stirred at 50° C. for 2 hours. Then,dichloromethane (20 mL) was added and the aqueous layer was extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated. The crude product waspurified by reverse phase high performance liquid chromatography using agradient of water and acetonitrile gradient (95:5 to 5:95) to give thetitle compound (14 mg, 40%) as white solid. ¹H NMR (400 MHz,methanol-d₄): δ 8.12 (s, 1H), 7.13 (d, 2H), 6.70 (d, 2H), 5.12-5.09 (m,1H), 3.34 (s, 3H), 3.34-3.33 (m, 2H), 3.20-3.17 (m, 2H), 2.64-2.61 (m,3H), 2.26-2.22 (m, 2H), 1.75-1.69 (m, 2H), 0.89-0.86 (m, 2H), 0.56-0.52(m, 2H), 0.18-0.17 (m, 2H). LC/MS (exact mass) calculated forC₁₇H₂₄N₄O₂S; 348.16. found (M+H⁺); 349.1.

Example 33N-[cis-3-({[(3,3-Difluorocyclobutyl)methyl]sulfonyl}-methyl)cyclobutyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineStep 1:N-[cis-3-({[(3,3-Difluorocyclobutyl)methyl]sulfanyl}methyl)cyclobutyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Nitrogen was bubbled through a mixture ofS-{[cis-3-(methyl{7-[(4-methylphenyl)-sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}ethanethioate,Example 25, Step 5 (250 mg, 0.56 mmol) and potassium carbonate (194 mg,1.41 mmol) in methanol (100 mL) for two minutes at 0° C. followed byaddition of (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate(prepared as described in WO2004/032834) (310 mg, 1.12 mmol). Themixture stirred for 6 hours at room temperature, filtered, andconcentrated to give the title compound (270 mg, crude) as white solid.LC/MS (exact mass) calculated for C₁₇H₂₂F₂N₄S; 352.15. found (M+H⁺);353.2.

Step 2:N-[cis-3-({[(3,3-Difluorocyclobutyl)methyl]sulfonyl}methyl)cyclobutyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The mixture ofN-[cis-3-({[(3,3-difluorocyclobutyl)methyl]sulfanyl}-methyl)cyclobutyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(45 mg, 0.13 mmol) and potassium peroxomonosulfate (157 mg, 0.26 mmol)in a mixture of tetrahydrofuran (20 mL), water (10 mL) and ethanol (20mL) was stirred at room temperature for 20 minutes. Aqueous sodiumbisulfite was then added, followed by dichloromethane (20 mL). Theaqueous layer was extracted with dichloromethane (2×20 mL) and thecombined organic layers were extracted with brine, dried over sodiumsulfate, and concentrated. The crude product was purified by reversephase high performance liquid chromatography using water-acetonitrilegradient (95:5 to 5:95) to give the title compound as white solid (34mg, 39%). ¹H NMR (400 MHz, methanol-d₄): δ 8.29 (s, 1H), 7.42 (d, 1H),7.03 (d, 1H), 4.86 (m, 1H), 3.51 (s, 3H), 3.39-3.33 (m, 4H), 2.84 (m,1H), 2.76-2.71 (m, 4H), 2.53 (m, 2H), 2.37-2.34 (m, 2H). LC/MS (exactmass) calculated for C₁₇H₂₂F₂N₄O₂S; 384.14. found (M+H⁺); 385.1.

Example 34A and 34B (1R,3R) and(1S,3S)-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]cyclopentanecarbonitrile

The title compound mixture of (1R,3R) and (15,3S)-3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methyl)sulfonyl]cyclopentanecarbonitrilewas prepared fromS-{[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}ethanethioateExample 25, Step 5, according to the procedure of Example 30, steps 1and 2.

The title compound (180 mg) was separated by preparative supercriticalfluid chromatography using a Chiralpak AS column:

(1R,3R) enantiomer 34A: 60 mg, ¹H NMR (400 MHz, methanol-d₄): δ 8.12 (s,1H), 7.13-7.12 (d, 1H), 6.70-6.69 (d, 1H), 5.17-5.11 (m, 1H), 3.86-3.78(m, 1H), 3.41-3.36 (m, 5H), 3.15-3.11 (m, 1H), 2.63-2.53 (m, 4H),2.37-2.13 (m, 6H), 2.03-1.91 (m, 1H). LC/MS (exact mass) calculated forC₁₇H₂₂F₂N₄O₂S; 373.16. found (M+H⁺); 374.1.

(1S,3S) enantiomer 34B: 27 mg, LC/MS (exact mass) calculated forC₁₇H₂₂F₂N₄O₂S; 373.16. found (M+H⁺); 374.1.

The intermediate 3-cyanocyclopentyl 4-methylbenzenesulfonate used instep-1 was prepared as shown below:

3-Cyanocyclopentyl 4-methylbenzenesulfonate

4-Methylbenzene-1-sulfonyl chloride (6.9 g, 36 mmol) andN,N-dimethylpyridin-4-amine (100 mg) were added to a solution ofcompound 3-hydroxycyclopentane-carbonitrile (J. Org. Chem. 2007, 72,7423) (2 g, 18 mmol) and triethylamine (5.5 g, 54 mmol) indichloromethane (100 mL). The reaction was stirred at room temperaturefor 15 hours and then quenched mixture was quenched by addition ofsaturated aqueous sodium bicarbonate solution (20 mL). The mixture wasextracted with dichloromethane (4×50 mL). The combined organic layerswere dried over magnesium sulfate and concentrated. The residue waschromatographed on silica gel by eluting with a mixture of petroleumether and ethyl acetate (1:1) to give the title compound as yellow oil(0.5 g, 11% yield). LC/MS (exact mass) calculated for C₁₃H₁₅NO₃S;265.08. found (M+23); 287.9.

Example 35 RacemicN-methyl-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfonyl}methyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineStep 1: tert-Butyl3-({[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}sulfanyl)pyrrolidine-1-carboxylate

The solution ofcis-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl4-methylbenzenesulfonate from Example 25, Step 4 (2 g, 3.7 mmol) wasstirred in N-methylpyrrolidine (40 mL). 1,8-Diazabicycloundec-7-ene(1.13 g, 7.4 mmol) and 3-mercapto-pyrrolidine-1-carboxylic acidtert-butyl ester (1.13 g, 5.6 mmol) were then added to the reactionmixture. The reaction was stirred at room temperature for 16 hours.Water (200 mL) and ethyl acetate (500 mL) were added. The aqueous layerwas extracted with ethyl acetate (2×500 mL). and the combined organiclayers were dried and concentrated under vacuum to give the titlecompound as a white solid (2.6 g, 118%). LC/MS (exact mass) calculatedfor C₂₈H₃₇N₅O₄S₂; 571.23. found (M+H⁺): 572.1.

Step 2:N-Methyl-7-[(4-methylphenyl)sulfonyl]-N-{cis-3-[(pyrrolidin-3-ylsulfanyl)methyl]cyclobutyl}-7H-pyrrolo[2,3-c]pyrimidin-4-amine

To a solution of tert-butyl3-({[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}sulfanyl)pyrrolidine-1-carboxylate(2.6 g, 4.5 mmol) in methanol (15 mL) was added 3M hydrochloric acidsolution in methanol (40 mL). The resulting solution was stirred at roomtemperature for 1 hour. The solution was concentrated to give the crudeproduct, which was purified by chromatography on silica gel eluting witha gradient of dichloromethane and methanol (100:0 to 85:15) to give thetitle compound as colorless oil (1.7 g, 52%). ¹H NMR (400 MHz,methanol-d₄): δ 8.21 (s, 1H), 7.99 (d, 2H), 7.56 (d, 1H), 7.37 (d, 2H),6.88 (d, 1H), 4.95-4.87 (m, 1H), 3.29 (s, 1H), 3.27 (s, 3H), 3.21-3.17(m, 1H), 3.04-3.96 (m, 1H), 2.92-29 (m, 1H), 2.72-2.01 (m, 3H),2.50-2.43 (m, 2H), 2.39 (s, 3H), 2.29-2.15 (m, 2H), 2.03-2.01 (m, 2H),1.98-1.65 (m, 1H). LC/MS (exact mass) calculated for C₂₃H₂₉N₅O₂S₂;471.18. found (M+23): 494.

Step 3:N-Methyl-7-[(4-methylphenyl)sulfonyl]-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfanyl}methyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution ofN-methyl-7-[(4-methylphenyl)sulfonyl]-N-{cis-3-[(pyrrolidin-3-ylsulfanyl)methyl]cyclobutyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine(472 mg, 1 mmol) in dichloromethane (50 mL) was added acetone (174 mg, 3mmol), 4A molecular sieves (40 mg) and sodium cyanoborohydride (189 mg,3 mmol). The resulting solution was stirred at room temperature for 1hour, then diluted with dichloromethane (70 mL) and water (70 mL). Theaqueous layer was extracted with dichloromethane (2×50 mL) and thecombined organic layers were washed with brine (100 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated to givetitle compound (500 mg, 97% yield) as colorless oil. LC/MS (exact mass)calculated for C₂₆H₃₅N₅O₂S₂; 513.22, found (M+H⁺); 514.1.

Step 4:N-Methyl-7-[(4-methylphenyl)sulfonyl]-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfonyl}methyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The mixture ofN-methyl-7-[(4-methylphenyl)sulfonyl]-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfanyl}methyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine_(500mg, 1.0 mmol) and potassium peroxomonosulfate (1.23 g, 2.0 mmol) intetrahydrofuran (20 mL), water (10 mL), and ethanol (20 mL) was stirredat room temperature for 30 minutes. The reaction solution was dilutedwith ethyl acetate (100 mL) and water (50 mL). The aqueous layer wasextracted with ethyl acetate (3×50 mL) and the combined organic layerswere washed with brine (100 mL), dried over sodium sulfate andconcentrated to give title compound as colorless oil (420 mg, 90%).LC/MS (exact mass) calculated for C₂₆H₃₅N₅O₄S₂; 545.21. found (M+H⁺):546.3.

Step 5:N-Methyl-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfonyl}methyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

The mixture ofN-methyl-7-[(4-methylphenyl)sulfonyl]-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfonyl}methyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine_(330mg, 0.6 mmol) and lithium hydroxide (126 mg, 3 mmol) in a mixture ofwater (5 mL) and ethanol (10 mL) was stirred at 50° C. for 2 hours. Themixture was then concentrated and the residue was taken up in ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The crude product was purified by reversephase high performance liquid chromatography using a gradient of waterand acetonitrile (95:5 to 5:95) to give the title compound (89 mg, 38%)as white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.32 (s, 1H), 7.07 (d, 1H),6.57 (d, 1H), 5.13 (m, 1H), 3.57 (m, 1H), 3.33 (s, 3H) 3.05-3.22 (m,3H), 2.92 (m, 1H), 2.78-2.87 (m, 1H), 2.58-2.77 (m, 4H), 2.50 (m, 1H),2.19-2.34 (m, 2H), 2.06-2.19 (m, 2H), 1.12 (d, 6H). LC/MS (exact mass)calculated for C₁₉H₂₉N₅O₂S; 391.20. found (M+H⁺); 392.3.

Example 36N-(cis-3-{[(3-Chloro-4-fluorophenyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amineStep 1:N-(cis-3-{[(3-Chloro-4-fluorophenyl)sulfanyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution of 3-chloro-4-fluorothiophenol (93 mg, 0.55 mmol) intetrahydrofuran (1.5 mL) was added 50% aqueous sodium hydroxide (44 mg,0.55 mmol) and ethanol (1.5 mL). The mixture was stirred at roomtemperature for 1 hour. A solution ofcis-[3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl4-methylbenzenesulfonate from Example 25, Step 4 (200 mg, 0.37 mmol) intetrahydrofuran (1.5 mL) was added to the reaction mixture. The combinedmixture was heated at 40° C. overnight. The reaction was concentratedand purified by silica column eluting with a gradient of heptanes andethyl acetate (90:10 to 0:100) to afford the title compound (69 mg,49.6%). ¹H NMR (400 MHz, CDCl₃): δ 8.18 (s, 1H), 7.39 (dd, 1H), 7.28 (s,1H), 7.03-7.08 (m, 1H), 7.00 (d, 1H), 6.52 (d, 1H), 4.97-5.07 (m, 1H),3.35 (m, 2H), 3.23 (s, 3H), 2.89 (s, 1H), 2.43-2.52 (m, 2H), 2.19-2.30(m, 2H).

Step 2:N-(cis-3-{[(3-Chloro-4-fluorophenyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

To a solution ofN-(cis-3-{[(3-chloro-4-fluorophenyl)sulfanyl]methyl}cyclobutyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(75 mg, 0.2 mmol) in dichloromethane (10 mL) was added3-chlorobenzoperoxoic acid (107 mg). The reaction was stirred at roomtemperature overnight and then concentrated. The crude residue waschromatographed on silica gel eluting with a gradient of dichloromethaneand 2M ammonia in methanol (80:20) to obtain the title compound (48 mg,59.2%). ¹H NMR (400 MHz, methanol-d₄): δ 8.31 (s, 1H), 8.02 (m, 1H),7.81-7.83 (m, 1H) 7.37-7.27 (m, 1H), 7.09 (d, 1H), 6.65 (s, 1H),5.18-5.10 (m, 1H), 4.15-4.09 (m, 1H), 3.32 (m, 5H), 2.59-2.54 (m, 2H),2.44-2.42 (m, 2H). LC/MS (exact mass) calculated for C₁₈H₁₈ClFN₄O₂S;408.08. found (M+H⁺); 409.

Example 372-[({cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyridine-4-carbonitrile Step 1:2-({[cis-3-(Methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}sulfanyl)pyridine-4-carbonitrile

1,8-Diazabicycloundec-7-ene (24.6 g, 161 mmol) and2-mercaptoisonicotinonitrile (16.1 g, 118 mmol) were added to a solutionof[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-methylmethanesulfonate (50 g, 110 mmol) in N-methylpyrrolidine (250 mL). Thereaction was heated at 50° C. overnight. Additional2-mercaptoisonicotinonitrile (8.1 g, 59 mmol) was added to drive thereaction to completion. The mixture was cooled to about 0° C. and thenthe reaction was quenched by dropwise addition of water. The solids werecollected by filtration, washed with water, and dried under vacuum at50° C. to give the title compound as a bright yellow solid (45.8 g,82.8%). LC/MS (exact mass) calculated for C₂₅H₂₄N₆O₂S₂; 504.14. found(M+H⁺); 505.1.

Step 2:2-[({cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfanyl]pyridine-4-carbonitrile

To a solution of2-({[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]methyl}sulfanyl)pyridine-4-carbonitrile(45.3 g, 89.8 mmol) in tetrahydrofuran (180 mL) was added a solution of1M tetrabutylammonium fluoride in tetrahydrofuran (269 mL). The reactionmixture was heated to reflux for 6 hours and then cooled to roomtemperature. Water was added dropwise over 45 minutes. The solids werecollected by filtration and washed with a mixture of 20% tetrahydrofuran(33 mL) and water (97 mL). The wet cake was dried under vacuum at 50° C.to give the title compound as a tan solid (25 g, 79%). LC/MS (exactmass) calculated for C₁₈H₁₈N₆S₂; 350.13. found (M+H⁺); 351.1.

Step 3:2-[({cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methyl)sulfonyl]pyridine-4-carbonitrile

Potassium peroxomonosulfate (236.8 g, 385.2 mmol) was added slowly to amixture of2-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-methyl)sulfanyl]pyridine-4-carbonitrile(22.5 g, 64.2 mmol) in methanol (337 mL) and water (56 mL) at 0° C. Thereaction was stirred at 3° C. for 20 hours. The reaction was quenchedusing 10% aqueous sodium bisulfate solution (40 mL). and the resultingslurry was stirred at room temperature for 2 hours. Aqueous 10%potassium carbonate solution was added until the pH was 4 to 5. Thematerial was filtered and rinsed with water. The wet filter cake wasdried under vacuum at 40° C. to give an off-white solid. This materialwas taken up in tetrahydrofuran (50 mL) and heated to reflux for 3hours. The mixture was cooled to room temperature and filtered tocollect the solid, which was dried under vacuum at 40° C. to the titlecompound as a light tan powder (17.3 g, 70.46%). ¹H NMR (400 MHz,CDCl₃): δ 11.97 (s, 1H), 8.95 (d, 1H), 8.33-8.28 (m, 2H), 7.81 (d, 1H)7.1 (d, 1H), 6.54 (d, 1H), 5.13-5.08 (m, 1H), 3.63 (m, 2H), 3.30 (s,3H), 2.54-2.48 (m, 3H), 2.09-2.07 (m, 2H). LC/MS (exact mass) calculatedfor C₁₈H₁₈N₆O₂S₂; 382.12. found (M+H⁺); 383.1.

Example 382-Methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1,3-thiazole-5-sulfonamideStep 1:2-Methyl-N-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-1,3-thiazole-5-sulfonamide

Triethylamine (62.0 g, 0.613 mol) is added to a solution ofcis-N-methyl-N-7H-pyrrolo[2,3-d]pyrimidin-4-ylcyclobutane-1,3-diaminehydrochloride (22.2 g, 0.102 mol) in dichloromethane (250 mL).2-Methylthiazole-5-sulfonyl chloride (28.0 g, 0.142 mol) indichloromethane (250 mL) is added over 30 minutes at room temperature tothe reaction mixture. After 1.5 hours the solvent is removed underreduced pressure and the resultant solid dissolved in 4:1ethyacetate:dichloromethane (400 mL). The solution is filtered through a40 g silica plug, rinsing with ethylacetate (800 mL) and dichloromethane(100 mL). The solvent from the filtrate is removed under reducedpressure to give solid (59 g). The solid is purified using silica gelcolumn chromatography eluting from 1:1 dichloromethane:ethylacetate toneat ethylacetate to give the title compound (44.4 g, 81%); m/z (Cl) 533[M+H]⁺.

Step 2:2-Methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1,3-thiazole-5-sulfonamide

Lithium hydroxide (12.1 g, 0.505 mol) in water (290 mL) is added to2-methyl-N-[cis-3-(methyl{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclobutyl]-1,3-thiazole-5-sulfonamide(43.8 g, 82.2 mmol) in isopropyl alcohol (435 mL) and the mixture heatedto 60° C. overnight. After cooling to room temperature the reactionmixture is filtered rinsing with water (145 mL). The filtrate is pH isadjusted to 6-7 using 6M aqueous hydrochloric acid. The reaction slurryis concentrated under reduced pressure. Water (370 mL) is added and themixture cooled to 0° C. The solved is collected by filtration, washedwith cold water (150 ml) then vacuum dried at 60° C. overnight to givethe title compound (25.0 g, 80%); ¹H NMR (DMSO-d6): δ 11.66-11.71 (1H),8.44-8.47 (1H), 8.11-8.08 (2H), 7.16-7.17 (1H), 6.63-6.65 (1H),4.86-4.94 (1H), 3.58-3.68 (1H), 3.22 (3H), 2.74 (3H), 2.40-2.46 (2H),2.10-2.18 (2H). m/z (Cl) 379 [M+H]⁺.

Biological Evaluation

JAK Caliper Enzyme Assay at 1 mM ATP

Test article was solubilized in dimethyl sulfoxide (DMSO) to a stockconcentration of 30 mM. An 11-point half log dilution series was createdin DMSO with a top concentration of 600 μM. The test compound plate alsocontained positive control wells containing a known inhibitor to define100% inhibition and negative control wells containing DMSO to define noinhibition. The compound plates were diluted 1 to 60 resulting in a topfinal assay compound concentration of 10 μM and a 2% DMSO concentration.

Test article and assay controls were added to a 384-well plate. Reactionmixtures contained 20 mM HEPES, pH 7.4, 10 mM magnesium chloride, 0.01%bovine serum albumin (BSA), 0.0005% Tween 20, 1 mM ATP and 1 μM peptidesubstrate. The JAK1 and TYK2 assays contained 1 μM of the IRStidepeptide (5FAMKKSRGDYMTMQID) and the JAK2 and JAK3 assays contained 1 μMof the JAKtide peptide (FITC-KGGEEEEYFELVKK). The assays were initiatedby the addition of 20 nM JAK1, 1 nM JAK2, 1 nM JAK3 or 1 nM TYK2 enzymeand were incubated at room temperature for three hours for JAK1, 60minutes for JAK2, 75 minutes for JAK3 or 135 minutes for TYK2. Enzymeconcentrations and incubation times were optimized for each new enzymepreps and were modified slightly over time to ensure 20%-30%phosphorylation. The assays were stopped with a final concentration of10 mM EDTA, 0.1% Coating Reagent and 100 mM HEPES, pH=7.4. The assayplates were placed on a Caliper Life Science Lab Chip 3000 (LC3000)instrument, and each well was sampled using appropriate separationconditions to measure the unphosphorylated and phosphorylated peptide.

TABLE 1 Data for JAK Caliper ™ Enzyme assay at 1 mM ATP. JAK1 JAK2 JAK3Tyk2 Structure Example IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)

 1 22 381 >9220 1020

 2 29 803 >10000 1250

 3 14 542 >10000 479

 4B 6 607 >10000 965

 4A 18 1400 >10000 2710

 5 6 313 8090 878

 6 28 933 >10000 2380

 7A 31 2020 >10000 5240

 7B 16 750 >10000 2440

 8 3 700 >10000 260

 9 231 5630 >10000 6670

10 1030 7180 >10000 >10000

11 29 574 5950 2040

12 6 413 >9670 770

13 5 177 8840 323

14 42 1200 >10000 1870

15 6 597 >10000 4910

16 51 1100 >10000 1780

17A 5 308 >10000 337

17B 13 434 >9770 1120

18 46 1080 >10000 7380

19 34 1150 >10000 2030

20 4 171 5500 332

21 1 52 3120 365

22 22 412 >10,000 1190

23 8 551 >10000 565

27 17 987 >10000 1970

24 241 3370 >10000 7870

25 9 373 >10000 713

26 6 88 1880 358

28 5 179 5270 444

29 17 372 >9930 1100

30 9 220 >6710 553

31 67 946 >10000 3610

32 14 426 >10000 1460

33 5 161 6570 582

34B 9 309 >10000 840

34A 37 801 >10000 3280

35 106 3760 >10000 >10000

36 4 85 3190 242

37 6 569 >8880 418

38 4.6 512 >10000 546

HWB INF Alpha Induced STAT3 Phosphorylation Assay

Test articles were prepared as 30 mM stocks in 100% DMSO, and thendiluted to 5 mM. A 10-point 2.5 dilution series was created in DMSO witha top concentration of 5 mM. Further dilution was done by adding 4 μL ofthe above test article solutions into 96 μL of PBS with a topconcentration of 200 μM.

To a 96-well polypropylene plate (VWR 82007-292) 90 μl of HWB was addedper well, followed by addition of 5 μl test article solutions preparedabove to give a top concentration of 10 μM. The plate was mixed andincubated for 45 minutes at 37° C. To each well was added 5 μl of humanIFN alpha (Universal Type I IFN, R&D Systems #11200-2; finalconcentration of 5000 U/ml) or D-PBS (unstimulated control), mixed andincubated 15 minutes at 37° C. The reaction was quenched by addingLyse/Fix Buffer [BD Phosflow 5× Lyse/Fix Buffer (BD #558049)] to allwells at 1000 μl/well and incubated for 20 minutes at 37° C.; afterwashing with FACS buffer [D-PBS (Invitrogen cat#14190) containing 0.1%BSA and 0.1% sodium azide], 400 μl ice cold 90% methanol/water was addedto each well and incubated on ice for 30 minutes. One more wash was donewith cold FACS buffer and all samples were finally resuspended in 250μl/well of the desired Alexa Fluor 647 conjugated anti-phospho-STAT3(pY705) antibody (BD #557815) at 1:125 dilution in FACS buffer. Afterovernight incubation at 4 degree all the samples were transferred into a96-well polypropylene U-bottom plate (Falcon #353077) and checked byflow cytometry machine. IC₅₀ values obtained for examples 1 to 9, 11-23,25-38 were in the range of 22 to 2610 nM.

Canine In Vitro T-Cell Proliferation Assay

T-cell activation plays a key role in a variety of inflammatory andautoimmune disorders as well as asthma, allergies and pruritus. SinceT-cell activation can, in part, can be triggered by cytokines thatsignal through the JAK-STAT pathway, a JAK inhibitor could be effectiveagainst such diseases involving aberrant T-cell activation.

Methods: Canine whole blood was collected in sodium heparin tubes from29 beagle dogs and 23 mixed breed dogs. Whole blood (20 μL) was platedin 96-well plates (Costar 3598) with 180 μL of medium (RPMI 1640, Gibco#21870-076, with 1% heat inactivated fetal bovine serum, Gibco#10082-39, 292 μg/ml L-glutamine, Gibco #250030-081, 100 u/ml penicillinand 1004 streptomycin per ml, Gibco #15140-122) containing vehiclecontrol or test compound (0.001 to 10 μM), concanavalin A (ConA; 1μg/ml, Sigma C5275), and canine interleukin-2 (IL-2; 50 ng/ml, R&DSystems 1815-CL/CF). Wells containing whole blood, medium with vehiclecontrol and no ConA or IL-2 were used as background controls. Plateswere incubated at 37° C. for 48 hours. Tritiated thymidine, 0.4 μCi/well(Perkin Elmer, Net027A-005MC), was added for 20 additional hours. Plateswere frozen and then thawed, washed and filtered using a Brandel MLR-96cell harvester and pre-wet filter mats (Wallac 1205-401, Perkin Elmer).Filters were dried at 60° C. for one hour (Precision 16EG convectionoven) and placed into filter sample bags (Wallac 1205-411, Perkin Elmer)with 10 mL of scintillant (Wallac 1205-440, Perkin Elmer). Sealedfilters were counted on a LKB Wallac 1205 Betaplate liquid scintillationcounter. Data were collected via Gterm Betaplate program v1.1 andtransformed into percent inhibition, calculated using the followingformula:

${ {100 - \frac{\lbrack {( {{Mean}\mspace{14mu} {Drug}\mspace{14mu} {Treatment}\mspace{14mu} {cpm}} ) - ( {{Mean}\mspace{14mu} {BCK}\mspace{14mu} {cpm}} )} \rbrack}{\lbrack {( {{Mean}\mspace{14mu} {Non}\mspace{14mu} {Drug}\mspace{14mu} {Treatment}\mspace{14mu} {cpm}} ) - ( {{Mean}\mspace{14mu} {BCK}\mspace{14mu} {cpm}} )} \rbrack}} \rbrack \times 100} = {\% \mspace{14mu} {Inhibition}}$

Data were graphically displayed as percent inhibition using GraphPadPrism 4.0, and IC₅₀ curves were fitted using a point to point analysis.

Example 38 had an IC₅₀ of 48.5 nM in this assay. This data suggests thatthe compounds of the present invention are effective in inhibitingT-cell proliferation, a key feature in diseases resulting from JAKdysregulation.

1-19. (canceled)
 20. A compound of formula I having the structure:

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen orC₁-C₄ alkyl, wherein said alkyl is further optionally substituted withone or more substituents selected from the group consisting of halo,hydroxy, methoxy, amino, CF₃, and C₃-C₆ cycloalkyl; X is selected from—NH— and —CR_(a)R_(b)—, where (a) R_(a) and R_(b) are independentlyhydrogen, deuterium, C₁-C₆ linear or branched chain alkyl, C₃-C₆cycloalkyl, aryl, (aryl)C₁-C₆ linear or branched chain alkyl,heteroaryl, (C₁-C₆ linear or branched chain alkyl)heteroaryl,(heteroaryl)C₁-C₆ linear or branched chain alkyl, (heterocyclic)C₁-C₆linear or branched chain alkyl, or (b) R_(a) and R_(b) together form achain comprising —(CR_(c)R_(d))_(j)—, where R_(c) and R_(d) areindependently hydrogen, deuterium, C₁-C₆ linear or branched chain alkyl,aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl, (C₁-C₆linear or branched chain alkyl)heteroaryl, halo, CN, CF₃, hydroxyl,CONH₂, or SO₂CH₃; Y is -A-R⁵, where A is a bond, —(CH₂)_(k)— or—(CD₂)_(k)— and R⁵ is C₁-C₆ linear or branched chain alkyl, C₃-C₆cycloalkyl, aryl, or —NR_(a′)R_(b′), or is an unsaturated, saturated orpartially saturated monocyclic or bicyclic ring structure containing atotal of four to eleven atoms having one to three heteroatomsindependently selected from the group consisting of oxygen, nitrogen,and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl, aryl, or monocyclic orbicyclic ring structure is further optionally substituted with one ormore substituents selected from the group consisting of deuterium, halo,C₁-C₆ linear or branched chain alkyl, CN, hydroxyl, CF₃, —OR_(e),—NR_(e)R_(f), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CONH₂, andSO₂CH₃, where (a) R_(a′) and R_(b′) are independently hydrogen,deuterium, C₁-C₆ linear or branched chain alkyl, C₃-C₆ cycloalkyl, aryl,(C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl, or (C₁-C₆ linearor branched chain alkyl)heteroaryl, where said alkyl and cycloalkyl maybe optionally substituted with one or more R_(c′) or (b) R_(a′) andR_(b′) together form a chain comprising —(CR_(c′)R_(d′))_(j)—, whereR_(c′) and R_(d′) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl,heteroaryl, (C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN,hydroxyl, CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); whereR_(e) and R_(f) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, or C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CF₃, andCONH₂; j is 2, 3, 4 or 5; k is 1, 2; 3, or 4; p is 0, 1 or 2; and, n is1 or
 2. 21. The compound of claim 20 which is a compound of formula IAhaving the structure:

or a pharmaceutically acceptable salt thereof, wherein Y is -A-R⁵, whereA is a bond, —(CH₂)_(k)— or —(CD₂)_(k)— and R⁵ is C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, or —NR_(a′)R_(b′), or isan unsaturated, saturated or partially saturated monocyclic or bicyclicring structure containing a total of five to eleven atoms having one tothree heteroatoms independently selected from the group consisting ofoxygen, nitrogen, and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl,aryl, or monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —OR_(e), —NR_(e)R_(f), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more substituents selected from the groupconsisting of halo, CN, hydroxyl, CONH₂, and SO₂CH₃, where (a) R_(a′)and R_(b′) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branchedchain alkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c′), or (b) R_(a′) and R_(b′) togetherform a chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl,(C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl,CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) andR_(f) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; j is 2, 3, 4 or5; k is 1, 2; 3, or 4; and, p is 0, 1 or
 2. 22. A compound of claim 21wherein A is a bond and R⁵ is a C₁-C₆ linear or branched chain alkyl,C₃-C₆ cycloalkyl or aryl.
 23. A compound of claim 21 wherein A is a bondor —(CH₂)_(k)—, and R⁵ is C₃-C₆ cycloalkyl wherein said C₃-C₆ cycloalkylis further optionally substituted with one or more substituents selectedfrom the group consisting of halo, C₁-C₆ linear or branched chain alkyl,and CN where said alkyl and cycloalkyl may be optionally substitutedwith one or more substituents selected from the group consisting ofhalo, CN, hydroxyl, CONH₂, and SO₂CH₃; where k is 1, 2, or
 3. 24. Acompound of claim 21 wherein A is a bond or —(CH₂)_(k)—, and R⁵ is anunsaturated, saturated or partially saturated monocyclic or bicyclicring structure containing a total of five to eleven atoms having one tothree heteroatoms independently selected from the group consisting ofoxygen, nitrogen, and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl,aryl, or monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —NR_(a′)R_(b′), —OR_(e), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl; where k is 1, 2, or
 3. 25. The compound of claim 20 which isa compound of formula IB having the structure:

or a pharmaceutically acceptable salt thereof, wherein (a) R_(a′) andR_(b′) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c); (b) R_(a′) and R_(b′) together forma chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′) areindependently hydrogen, deuterium, C₁-C₆ linear or branched chain alkyl,aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl, (C₁-C₆linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF₃,CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) and R_(f)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; or, (c) R_(a′)and R_(b′) together form an unsaturated, saturated or partiallysaturated monocyclic or bicyclic ring structure containing a total offive to eleven atoms having one to three heteroatoms independentlyselected from the group consisting of oxygen, nitrogen, and sulfur,wherein said monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —NR_(e)R_(f), —OR_(e), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl; j is 2, 3, 4 or 5; and, p is 0, 1 or
 2. 26. The compound ofclaim 20 which is a compound of formula IB having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(a′) and R_(b′)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c).
 27. The compound of claim 20 whichis a compound of formula IB having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(a′) and R_(b′)together form a chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) andR_(d′) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl,heteroaryl, (C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN,hydroxyl, CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); whereR_(e) and R_(f) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, or C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CF₃, andCONH₂; and, j is 2, 3, 4 or 5; and, p is 0, 1 or
 2. 28. The compound ofclaim 20 which is a compound of formula IB having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(a′) and R_(b′)together form an unsaturated, saturated or partially saturatedmonocyclic or bicyclic ring structure containing a total of five toeleven atoms having one to three heteroatoms independently selected fromthe group consisting of oxygen, nitrogen, and sulfur, wherein saidmonocyclic or bicyclic ring structure is further optionally substitutedwith one or more substituents selected from the group consisting ofdeuterium, halo, C₁-C₆ linear or branched chain alkyl, CN, hydroxyl,CF₃, —NR_(e)R_(f), —OR_(e), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl; and, pis 0, 1 or
 2. 29. The compound of claim 20 which is a compound offormula IC having the structure:

or a pharmaceutically acceptable salt thereof, wherein (a) R_(a′) andR_(b′) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c); (b) R_(a′) and R_(b′) together forma chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′) areindependently hydrogen, deuterium, C₁-C₆ linear or branched chain alkyl,aryl, (C₁-C₆ linear or branched chain alkyl)aryl, heteroaryl, (C₁-C₆linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF₃,CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) and R_(f)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; or, (c) R_(a′)and R_(b′) together form an unsaturated, saturated or partiallysaturated monocyclic or bicyclic ring structure containing a total offive to eleven atoms having one to three heteroatoms independentlyselected from the group consisting of oxygen, nitrogen, and sulfur,wherein said monocyclic or bicyclic ring structure is further optionallysubstituted with one or more substituents selected from the groupconsisting of deuterium, halo, C₁-C₆ linear or branched chain alkyl, CN,hydroxyl, CF₃, —NR_(e)R_(f), —OR_(e), —S(O)_(p)R_(e) and C₃-C₆cycloalkyl; j is 2, 3, 4 or 5; and, p is 0, 1 or
 2. 30. The compound ofclaim 20 which is a compound of formula IC having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(a′) and R_(b′)are independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, C₃-C₆ cycloalkyl, aryl, (C₁-C₆ linear or branched chainalkyl)aryl, heteroaryl, or (C₁-C₆ linear or branched chainalkyl)heteroaryl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more R_(c).
 31. The compound of claim 20 whichis a compound of formula IC having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(a′) and R_(b′)together form a chain comprising —(CR_(c′)R_(d′))_(j)—, where R_(c′) andR_(d′) are independently hydrogen, deuterium, C₁-C₆ linear or branchedchain alkyl, aryl, (C₁-C₆ linear or branched chain alkyl)aryl,heteroaryl, (C₁-C₆ linear or branched chain alkyl)heteroaryl, halo, CN,hydroxyl, CF₃, CONH₂, —OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); whereR_(e) and R_(f) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, or C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CF₃, andCONH₂; j is 2, 3, 4 or 5; and, p is 0, 1 or 2
 32. The compound of claim20 which is a compound of formula IC having the structure:

or a pharmaceutically acceptable salt thereof, wherein R_(a′) and R_(b′)together form an unsaturated, saturated or partially saturatedmonocyclic or bicyclic ring structure containing a total of five toeleven atoms having one to three heteroatoms independently selected fromthe group consisting of oxygen, nitrogen, and sulfur, wherein saidmonocyclic or bicyclic ring structure is further optionally substitutedwith one or more substituents selected from the group consisting ofdeuterium, halo, C₁-C₆ linear or branched chain alkyl, CN, hydroxyl,CF₃, —NR_(e)R_(f), —OR_(e), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl; and, pis 0, 1 or
 2. 33. The compound of claim 20 which is a compound offormula ID having the structure:

or a pharmaceutically acceptable salt thereof, wherein Y is -AR⁵, whereA is a bond or —(CH₂)_(k)—, and R⁵ is C₁-C₆ linear or branched chainalkyl, C₃-C₆ cycloalkyl, aryl, or is an unsaturated, saturated orpartially saturated monocyclic or bicyclic ring structure containing atotal of five to eleven atoms having one to three heteroatomsindependently selected from the group consisting of oxygen, nitrogen,and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl, aryl, or monocyclic orbicyclic ring structure is further optionally substituted with one ormore substituents selected from the group consisting of deuterium, halo,C₁-C₆ linear or branched chain alkyl, CN, hydroxyl, CF₃, —S(O)_(p)R_(e)and C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may be optionallysubstituted with one or more substituents selected from the groupconsisting of halo, CN, hydroxyl, CONH₂, and SO₂CH₃, where (a) R_(a′)and R_(b′) are independently hydrogen, deuterium, C₁-C₆ linear orbranched chain alkyl, C₃-C₆ cycloalkyl, aryl, (aryl)C₁-C₆ linear orbranched chain alkyl, heteroaryl, C₆ linear or branched chainalkyl)heteroaryl, (heteroaryl)C₁-C₆ linear or branched chain alkyl,(heterocyclic)C₁-C₆ linear or branched chain alkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more R_(c′), or (b)R_(a′) and R_(b′) together form a chain comprising—(OR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′) are independentlyhydrogen, deuterium, C₁-C₆ linear or branched chain alkyl, aryl, (C₁-C₆linear or branched chain alkyl)aryl, heteroaryl, (C₁-C₆ linear orbranched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF₃, CONH₂,—OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) and R_(f) whereare independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; j is 2, 3, 4 or5; k is 1, 2, or 3; and, p is 0, 1 or
 2. 34. The compound of claim 20which is a compound of formula ID having the structure:

or a pharmaceutically acceptable salt thereof, wherein Y is -AR⁵, whereA is a bond or —(CH₂)_(k)—, and R⁵ is C₁-C₆ linear or branched chainalkyl, C₃-C₆ cycloalkyl, aryl, or is an unsaturated, saturated orpartially saturated monocyclic or bicyclic ring structure containing atotal of five to eleven atoms having one to three heteroatomsindependently selected from the group consisting of oxygen, nitrogen,and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl, aryl, or monocyclic orbicyclic ring structure is further optionally substituted with one ormore substituents selected from the group consisting of deuterium, halo,C₁-C₆ linear or branched chain alkyl, CN, hydroxyl, CF₃, —NR_(a′)R_(b′),—OR_(e), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CONH₂, andSO₂CH₃, where R_(a′) and R_(b′) are independently hydrogen, deuterium,C₁-C₆ linear or branched chain alkyl, C₃-C₆ cycloalkyl, aryl,(aryl)C₁-C₆ linear or branched chain alkyl, heteroaryl, (C₁-C₆ linear orbranched chain alkyl)heteroaryl, (heteroaryl)C₁-C₆ linear or branchedchain alkyl, (heterocyclic)C₁-C₆ linear or branched chain alkyl, wheresaid alkyl and cycloalkyl may be optionally substituted with one or moreR_(c′), k is 1, 2, or 3; and, p is 0, 1 or
 2. 35. The compound of claim20 which is a compound of formula ID having the structure:

or a pharmaceutically acceptable salt thereof, wherein Y is -AR⁵, whereA is a bond or —(CH₂)_(k)—, and R⁵ is C₁-C₆ linear or branched chainalkyl, C₃-C₆ cycloalkyl, aryl, or is an unsaturated, saturated orpartially saturated monocyclic or bicyclic ring structure containing atotal of five to eleven atoms having one to three heteroatomsindependently selected from the group consisting of oxygen, nitrogen,and sulfur, wherein said alkyl, C₃-C₆ cycloalkyl, aryl, or monocyclic orbicyclic ring structure is further optionally substituted with one ormore substituents selected from the group consisting of deuterium, halo,C₁-C₆ linear or branched chain alkyl, CN, hydroxyl, CF₃, —NR_(a′)R_(b′),—OR_(e), —S(O)_(p)R_(e) and C₃-C₆ cycloalkyl, where said alkyl andcycloalkyl may be optionally substituted with one or more substituentsselected from the group consisting of halo, CN, hydroxyl, CONH₂, andSO₂CH₃, where R_(a′) and R_(b′) together form a chain comprising—(CR_(c′)R_(d′))_(j)—, where R_(c′) and R_(d′) are independentlyhydrogen, deuterium, C₁-C₆ linear or branched chain alkyl, aryl, (C₁-C₆linear or branched chain alkyl)aryl, heteroaryl, (C₁-C₆ linear orbranched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF₃, CONH₂,—OR_(e), —NR_(e)R_(f), or —S(O)_(p)R_(e); where R_(e) and R_(f) whereare independently hydrogen, deuterium, C₁-C₆ linear or branched chainalkyl, or C₃-C₆ cycloalkyl, where said alkyl and cycloalkyl may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, CN, hydroxyl, CF₃, and CONH₂; j is 2, 3, 4 or5; k is 1, 2, or 3; and, p is 0, 1 or
 2. 36. The compound of claim 20which is a compound of formula ID having the structure:

or a pharmaceutically acceptable salt thereof, wherein Y is -AR⁵, whereA is a bond or —(CH₂)_(k)—, and R⁵ is C₁-C₆ linear or branched chainalkyl, where said alkyl may be optionally substituted with one or moresubstituents selected from the group consisting of halo, CN, hydroxyl,CONH₂, and SO₂CH₃; and, k is 1, 2, or
 3. 37. A pharmaceuticalcomposition comprising a compound of claim 20, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.